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6/29/23, 11:41 PM SELECT-D Pathway Feedback Search Clinical Topics Home Studies SELECT D SELECT D Disease Disease Disease Cancer-associated thrombosis Deep vein thrombosis Pulmonary Reference Young AM, Marshall A, Thirlwall J et al. Comparison of an Oral Factor Xa Inhibitor With Low Molecular Weight Heparin in Patients With Cancer With Venous Thromboembolism: Results of a Randomized Trial (SELECT-D). J Clin Oncol. 2018 Jul 10;36(20):2017-2023. Open reference URL https://web.pathway.md/studies/recIE1gKA4CrDRcCG 1/1

6/29/23, 11:41 PM SEPSISPAM Pathway Feedback Search Clinical Topics Home Studies SEPSISPAM SEPSISPAM Disease Sepsis and septic shock Trial question What is the role of high blood-pressure target in patients with septic shock? Study design Multi-center Open label RCT Population Characteristics of study participants 33.0% female N = 776 67.0% male 776 patients (259 female, 517 male) Inclusion criteria: patients with septic shock Key exclusion criteria: legal protection (i.e., incompetence to provide consent and no guardian or incarceration), pregnancy, recent participation in another biomedical study or another interventional study with mortality as the primary end point, or an investigator's decision not to resuscitate Interventions N=388 high-target (mean arterial pressure target of 80-85 mmHg) N=388 low-target (mean arterial pressure target of 65-70 mmHg) Primary outcome https://web.pathway.md/studies/rec8grxZnrJmduGWd 1/2 6/29/23, 11:42 PM SEPSISPAM Pathway Death at 28 days 36.6 % 36.6 34 27.5 % 18.3 % 9.2 % No significant difference 0.0 % High-target Low-target No significant difference in death at 28 days (36.6% vs. 34%; HR 1.07, 95% CI 0.84 to 1.38) Secondary outcomes No significant difference in death at 90 days (43.8% vs. 42.3%; HR 1.04, 95% CI 0.83 to 1.3) Safety outcomes No significant differences in serious adverse events (19.1% vs. 17.8%, p=0.64). Significant differences in newly diagnosed AF (6.7% vs. 2.8%, p = 0.02). Conclusion In patients with septic shock, high-target was not superior to low-target with respect to death at 28 days. Reference Asfar P, Meziani F, Hamel JF et al. High versus low blood-pressure target in patients with septic shock. N Engl J Med. 2014 Apr 24;370(17):1583-93. Open reference URL https://web.pathway.md/studies/rec8grxZnrJmduGWd 2/2

6/29/23, 11:41 PM SETPOINT2 Pathway Feedback Search Clinical Topics Home Studies SETPOINT2 SETPOINT2 Disease Disease Disease Acute ischemic stroke Intracerebral hemorrhage Subarachn Trial question Is a strategy of early tracheostomy superior to the standard strategy in patients with severe stroke receiving mechanical ventilation? Study design Multi-center Open label RCT Population Characteristics of study participants 50.0% female N = 380 50.0% male 380 patients (189 female, 191 male) Inclusion criteria: patients with severe acute ischemic or hemorrhagic stroke receiving invasive ventilation Key exclusion criteria: premorbid mRS score > 1; invasive mechanical ventilation > 4 days; clinical condition either prohibiting early tracheostomy or mandating a surgical tracheostomy; pregnancy; life expectancy < 3 weeks Interventions N=188 early tracheostomy strategy (tracheostomy within 5 days of intubation) N=194 standard tracheostomy strategy (tracheostomy from day 10) https://web.pathway.md/studies/rec6h32GOYDNbxkmC 1/2 6/29/23, 11:41 PM SETPOINT2 Pathway Primary outcome Poor functional outcome as measured by a modified Rankin Scale score of < 4 at 6 months 47.1 % 47.1 43.5 35.3 % 23.6 % 11.8 % No significant difference 0.0 % Early tracheostomy strategy Standard tracheostomy strategy No significant difference in poor functional outcome as measured by a mRS score of < 4 at 6 months (43.5% vs. 47.1%; ARD -3.6, 95% CI -14.3 to 7.2) Secondary outcomes No significant difference in favorable functional outcome as measured by a mRS score of 0-3 at 6 months (24.3% vs. 19.6%; AD 4.7%, 95% CI -4.3 to 13.7) No significant difference in death in the ICU (14% vs. 14.9%; HR 0.94, 95% CI 0.65 to 1.35) No significant difference in time to discharge from hospital (24 days vs. 26 days; HR 0.94, 95% CI 0.76 to 1.18) Safety outcomes No significant difference in serious adverse events. Conclusion In patients with severe acute ischemic or hemorrhagic stroke receiving invasive ventilation, early tracheostomy strategy was not superior to standard tracheostomy strategy with respect to poor functional outcome as measured by a mRS score of < 4 at 6 months. Reference Julian B sel, Wolf-Dirk Niesen, Farid Salih et al. Effect of Early vs Standard Approach to Tracheostomy on Functional Outcome at 6 Months Among Patients With Severe Stroke Receiving Mechanical Ventilation: The SETPOINT2 Randomized Clinical Trial. JAMA. 2022 May 17;327(19):1899-1909. Open reference URL https://web.pathway.md/studies/rec6h32GOYDNbxkmC 2/2

6/29/23, 11:41 PM SHARP Pathway Feedback Search Clinical Topics Home Studies SHARP SHARP Disease Disease Chronic kidney disease Dyslipidemia Trial question What is the role of simvastatin plus ezetimibe in patients with advanced CKD? Study design Multi-center Double blinded RCT Population Characteristics of study participants 37.0% female N = 9270 63.0% male 9270 patients (3470 female, 5800 male) Inclusion criteria: patients with advanced CKD Key exclusion criteria: history of MI or coronary revascularization procedure, history of chronic liver disease, active inflammatory muscle disease, previous adverse reaction to a statin or to ezetimibe, concurrent treatment with a contraindicated drug, or child-bearing potential Interventions N=4650 simvastatin plus ezetimibe (20 mg simvastatin and 10 mg ezetimibe daily) N=4620 placebo (matching placebo daily) Primary outcome Major atherosclerotic events https://web.pathway.md/studies/recCX2JiFqmVbhuyK 1/2 6/29/23, 11:41 PM SHARP Pathway 13.4 % 13.4 11.3 10.1 % 6.7 % Significant decrease 3.4 % NNT = 48 0.0 % Simvastatin plus ezetimibe Placebo Significant decrease in major atherosclerotic events (11.3% vs. 13.4%; RR 0.83, 95% CI 0.74 to 0.94) Secondary outcomes No significant difference in nonfatal myocardial infarction or death from coronary artery disease (4.6% vs. 5%; RR 0.92, 95% CI 0.76 to 1.11) Significant decrease in non-hemorrhagic stroke (2.8% vs. 3.8%; RR 0.75, 95% CI 0.6 to 0.94) Significant decrease in arterial revascularisation procedures (6.1% vs. 7.6%; RR 0.79, 95% CI 0.68 to 0.93) Safety outcomes No significant differences in excess risk of myopathy (0.2% vs. 0.1%), hepatitis (0.5% vs. 0.4%) gallstones (2.3% vs. 2.3%), or cancer (9.4% vs. 9.5%, p=0.89), or excess of death from any non- vascular cause (14.4% vs. 13.2%, p=0.13). Conclusion In patients with advanced CKD, simvastatin plus ezetimibe was superior to placebo with respect to major atherosclerotic events. Reference Baigent C, Landray MJ, Reith C et al. The effects of lowering LDL cholesterol with simvastatin plus ezetimibe in patients with chronic kidney disease (Study of Heart and Renal Protection): a randomised placebo-controlled trial. Lancet. 2011 Jun 25;377(9784):2181-92. Open reference URL https://web.pathway.md/studies/recCX2JiFqmVbhuyK 2/2

6/29/23, 11:41 PM SHIFT Pathway Feedback Search Clinical Topics Home Studies SHIFT SHIFT Disease Heart failure Trial question What is the effect of ivabradine on heart-rate reduction in patients with chronic HF? Study design Multi-center Double blinded RCT Population Characteristics of study participants 23.2% female N = 6558 76.8% male 6558 patients (1535 female, 4970 male) Inclusion criteria: patients with symptomatic HF and a left-ventricular ejection fraction < 35% who were in sinus rhythm with HR 70 beats/min and had been admitted to hospital for HF within the previous year Key exclusion criteria: recent (< 2 months) myocardial infarction, ventricular or atrioventricular pacing operative for 40% of the day, AF or flutter, and symptomatic hypotension Interventions N=3268 ivabradine (titrated to a maximum of 7.5 mg BID) N=3290 placebo (matching placebo BID) Primary outcome https://web.pathway.md/studies/rec70ZHrZLoUIyQO3 1/2 6/29/23, 11:41 PM SHIFT Pathway Cardiovascular death or hospital admission for worsening heart failure 29.0 % 29 24 21.8 % 14.5 % Significant decrease 7.3 % NNT = 20 0.0 % Ivabradine Placebo Significant decrease in cardiovascular death or hospital admission for worsening HF (24% vs. 29%; HR 0.82, 95% CI 0.75 to 0.9) Secondary outcomes Significant decrease in hospital admission for worsening HF (21% vs. 16%; HR 0.74, 95% CI 0.66 to 0.83) Significant decrease in death due to HF (5% vs. 3%; HR 0.74, 95% CI 0.58 to 0.94) Safety outcomes Significant differences in serious adverse events (3388 vs. 3847, p = 0.025), symptomatic bradycardia (5% vs. 1%, p < 0.0001), and visual side-effects (3% vs. 1%, p < 0.0001). Conclusion In patients with symptomatic HF and a left-ventricular ejection fraction < 35% who were in sinus rhythm with HR 70 beats/min and had been admitted to hospital for HF within the previous year, ivabradine was superior to placebo with respect to cardiovascular death or hospital admission for worsening HF. Reference Swedberg K, Komajda M, Bohm M et al. Ivabradine and outcomes in chronic heart failure (SHIFT): a randomised placebo-controlled study. Lancet. 2010 Sep 11;376(9744):875-85. Open reference URL https://web.pathway.md/studies/rec70ZHrZLoUIyQO3 2/2

6/29/23, 11:41 PM SHINE Pathway Feedback Search Clinical Topics Home Studies SHINE SHINE Disease Disease Extrapulmonary tuberculosis Pulmonary tuberculosis Trial question Is 4 months antituberculosis treatment noninferior to 6 months treatment for children with non- severe tuberculosis? Study design Multi-center Open label RCT Population Characteristics of study participants 48.0% female N = 1204 52.0% male 1204 patients (583 female, 621 male) Inclusion criteria: children with non-severe, symptomatic, presumed drug-susceptible tuberculosis Key exclusion criteria: children with confirmed drug resistance; known exposure to an adult with any drug-resistant tuberculosis Interventions N=602 4 months treatment (first-line antituberculosis treatment with pediatric fixed-dose combinations as recommended by the WHO for 16 weeks) N=602 6 months treatment (first-line antituberculosis treatment with pediatric fixed-dose combinations as recommended by the WHO for 24 weeks) https://web.pathway.md/studies/recm9rDFN1vG3pQPK 1/2 6/29/23, 11:41 PM SHINE Pathway Primary outcome Treatment failure or disease recurrence at 72 weeks 3.0 % 3 3 2.3 % 1.5 % Difference not exceeding nonferiority margin 0.8 % 0.0 % 4 months treatment 6 months treatment Difference not exceeding nonferiority margin in treatment failure or disease recurrence at 72 weeks (3% vs. 3%; ARD -0.3, 95% CI -2.2 to 1.5) Safety outcomes No significant difference in grade 3 adverse events at 30 days post-treatment. Conclusion In children with non-severe, symptomatic, presumed drug-susceptible tuberculosis, 4 months treatment was noninferior to 6 months treatment with respect to treatment failure or disease recurrence at 72 weeks. Reference Anna Turkova, Genevieve H Wills, Eric Wobudeya et al. Shorter Treatment for Nonsevere Tuberculosis in African and Indian Children. N Engl J Med. 2022 Mar 10;386(10):911-922. Open reference URL https://web.pathway.md/studies/recm9rDFN1vG3pQPK 2/2

6/29/23, 11:42 PM SHoC-ED Pathway Feedback Search Clinical Topics Home Studies SHoC ED SHoC ED Trial question What is the role of point-of-care ultrasonography protocol in emergency department patients with undifferentiated hypotension? Study design Multi-center Open label RCT Population Characteristics of study participants 49.0% female N = 273 51.0% male 273 patients (135 female, 138 male) Inclusion criteria: patients who presented to the emergency department with undifferentiated nontraumatic hypotension or shock Key exclusion criteria: pregnancy, necessity of CPR or other advanced cardiac life support interventions before enrollment, history of significant trauma in the past 24 hours, clear mechanism of shock Interventions N=138 point-of-care ultrasonography (early point-of-care ultrasonography scans plus standard care) N=135 control (usual care without any point-of-care ultrasonography) Primary outcome Rate of survival to 30 days or hospital discharge 76.5 % 76.5 76.1 57.4 % 38.3 % https://web.pathway.md/studies/reclj1361vpWshrAn 1/2 6/29/23, 11:42 PM 38 3 % SHoC-ED Pathway 19.1 % No significant difference 0.0 % Point-of-care ultrasonography Control No significant difference in the rate of survival to 30 days or hospital discharge (76.5% vs. 76.1%; AD 0.35%, 95% CI -10.2 to 11) Secondary outcomes No significant difference in intravenous fluid administration (1609 mL vs. 1683 mL; AD 74 mL, 95% CI -50.8 to 196.2) No significant difference in hospital length of stay (9.59 days vs. 9.71 days; AD 0.12 days, 95% CI -1.74 to 2.36) No significant difference in ICU length of stay (7.16 days vs. 5.14 days; AD 2.018 days, 95% CI -0.85 to 4.63) Safety outcomes No significant difference in rates of CT scanning and rates of inotrope administration. Conclusion In patients who presented to the emergency department with undifferentiated nontraumatic hypotension or shock, point-of-care ultrasonography was not superior to control with respect to the rate of survival to 30 days or hospital discharge. Reference Paul R Atkinson, James Milne, Laura Diegelmann et al. Does Point-of-Care Ultrasonography Improve Clinical Outcomes in Emergency Department Patients With Undifferentiated Hypotension? An International Randomized Controlled Trial From the SHoC-ED Investigators. Ann Emerg Med. 2018 Oct;72(4):478-489. Open reference URL https://web.pathway.md/studies/reclj1361vpWshrAn 2/2

6/29/23, 11:42 PM SHOCK Pathway Feedback Search Clinical Topics Home Studies SHOCK SHOCK Disease Disease Cardiogenic shock ST-elevation myocardial infarction Trial question What is the effect of emergency revascularization in patients with shock due to LV failure complicating myocardial infarction? Study design Multi-center Open label RCT Population Characteristics of study participants 32.0% female N = 302 68.0% male 302 patients (97 female, 205 male) Inclusion criteria: patients with shock due to LV failure complicating myocardial infarction Key exclusion criteria: severe systemic illness, mechanical or other cause of shock, severe valvular disease, dilated cardiomyopathy, and unsuitability for revascularization Interventions N=152 emergency revascularization (CABG or angioplasty within 6 hours of randomization, intraaortic balloon counterpulsation recommended) N=150 initial medical stabilization (intensive medical treatment, intraaortic balloon counterpulsation recommended) https://web.pathway.md/studies/recIASDj4i32ml4we 1/2 6/29/23, 11:42 PM SHOCK Pathway Primary outcome Death at 30 days 56.0 % 56 46.7 42.0 % 28.0 % 14.0 % No significant difference 0.0 % Emergency revascularization Initial medical stabilization No significant difference in death at 30 days (46.7% vs. 56%; RR 0.83, 95% CI 0.67 to 1.04) Secondary outcomes Significant decrease in death at 6 months (50.3% vs. 63.1%; RR 0.8, 95% CI 0.65 to 0.98) Safety outcomes No significant difference in adverse events. Significant difference in acute renal failure (13% vs. 24%). Conclusion In patients with shock due to LV failure complicating myocardial infarction, emergency revascularization was not superior to initial medical stabilization with respect to death at 30 days. Reference Hochman JS, Sleeper LA, Webb JG et al. Early revascularization in acute myocardial infarction complicated by cardiogenic shock. SHOCK Investigators. Should We Emergently Revascularize Occluded Coronaries for Cardiogenic Shock. N Engl J Med. 1999 Aug 26;341(9):625-34. Open reference URL https://web.pathway.md/studies/recIASDj4i32ml4we 2/2

6/29/23, 11:42 PM SHOCKEM-Blue Pathway Feedback Search Clinical Topics Home Studies SHOCKEM Blue SHOCKEM Blue Disease Sepsis and septic shock Trial question What is the role of early adjunctive methylene blue in patients with septic shock? Study design Single center Double blinded RCT Population Characteristics of study participants 40.0% female N = 91 60.0% male 91 patients (36 female, 55 male) Inclusion criteria: adult patients with septic shock according to Sepsis-3 criteria Key exclusion criteria: > 24 hours since initiation of norepinephrine; pregnancy; high probability of death within 48 hours; concurrent hemorrhagic, obstructive or hypovolemic shock; pending damage control surgery; major burn injury Interventions N=45 methylene blue (intravenous infusion at a dose of 100 mg in 500 mL of 0.9% sodium chloride solution for 6 hours once a day for a total of 3 doses) N=46 placebo (intravenous infusion of 500 mL of 0.9% sodium chloride solution for 6 hours once a day for a total of 3 doses) https://web.pathway.md/studies/recEu3HuldvHskcwK 1/2 6/29/23, 11:42 PM SHOCKEM-Blue Pathway Primary outcome Time to vasopressor discontinuation at day 28 94.0 hours 94 70.5 hours 69 47.0 hours 23.5 hours Significant decrease 0.0 hours Methylene blue Placebo Significant decrease in time to vasopressor discontinuation at day 28 (69 hours vs. 94 hours; AD -25 hours, 95% CI -39.83 to -10.17) Secondary outcomes Significant increase in median vasopressor-free days at 28 days (23.9 days vs. 19.5 days; MD 4.4, 95% CI 1.15 to 7.65) Significant decrease in hospital length of stay (9 days vs. 10.5 days; AD -1.5 days, 95% CI -2.83 to -0.17) No significant difference in death at day 28 (33% vs. 46%; RR 0.76, 95% CI 0.55 to 1.05) Safety outcomes No significant differences in ejection fraction, serum creatinine, bilirubin, and liver aminotransferases. Significant difference in metHgb saturation (2.9% vs. 0.5%). Conclusion In adult patients with septic shock according to Sepsis-3 criteria, methylene blue was superior to placebo with respect to time to vasopressor discontinuation at day 28. Reference Miguel Ibarra-Estrada, Eduardo Kattan, Pavel Aguilera-Gonz lez et al. Early adjunctive methylene blue in patients with septic shock: a randomized controlled trial. Crit Care. 2023 Mar 13;27(1):110. Open reference URL https://web.pathway.md/studies/recEu3HuldvHskcwK 2/2

6/29/23, 11:42 PM SHORT Pathway Feedback Search Clinical Topics Home Studies SHORT SHORT Disease Febrile neutropenia Trial question Is short antibiotic treatment noninferior to extended antibiotic treatment with carbapenems in patients with high-risk fever of unknown origin during chemotherapy-induced neutropenia? Study design Multi-center Open label RCT Population Characteristics of study participants 39.0% female N = 281 61.0% male 281 patients (109 female, 172 male) Inclusion criteria: adult patients who had fever of unknown origin during high-risk neutropenia and were treated for hematological malignancy Key exclusion criteria: contraindication to use of imipenem-cilastatin or meropenem; corticosteroid use 10 mg/day prednisolone or equivalent for > 3 consecutive day during the previous 7 days; infection; symptoms of septic shock Interventions N=144 short treatment (500 mg intravenous imipenem-cilastatin QID or 1,000 mg intravenous meropenem TID for 72 hours) https://web.pathway.md/studies/recQt8lZcKWp1ZR6P 1/2 6/29/23, 11:42 PM SHORT Pathway N=137 extended treatment (500 mg intravenous imipenem-cilastatin QID or 1,000 mg intravenous meropenem TID for 9 days) Primary outcome Carbapenem -sensitive infection or recurrent fever 19.0 % 19 15 14.3 % 9.5 % Difference not exceeding nonferiority margin 4.8 % 0.0 % Short treatment Extended treatment Difference not exceeding nonferiority margin in carbapenem -sensitive infection or recurrent fever (19% vs. 15%; AD 4%, 90% CI -1.7 to 9.7) Secondary outcomes Significant increase in the rate of death within 30 days after the end of neutropenia (3% vs. 1%; AD 2.6%, 95% CI 1.2 to 4.1) Safety outcomes Significant difference in serious adverse events (16% vs. 10%). Conclusion In adult patients who had fever of unknown origin during high-risk neutropenia and were treated for hematological malignancy, short treatment was noninferior to extended treatment with respect to carbapenem -sensitive infection or recurrent fever. Reference Nick A de Jonge, Jonne J Sikkens, Sonja Zweegman et al. Short versus extended treatment with a carbapenem in patients with high-risk fever of unknown origin during neutropenia: a non-inferiority, open-label, multicentre, randomised trial. Lancet Haematol. 2022 Jun 9;S2352-3026(22)00145-4. Open reference URL https://web.pathway.md/studies/recQt8lZcKWp1ZR6P 2/2

6/29/23, 11:42 PM SHORTEN Pathway Feedback Search Clinical Topics Home Studies SHORTEN SHORTEN Disease Disease Antimicrobial-resistant Gram-ne Sepsis and septic shock Trial question Is a 7-day course of antibiotics superior to a 14-day course of antibiotics in patients with bloodstream infections caused by Enterobacterales? Study design Multi-center Open label RCT Population Characteristics of study participants 47.5% female N = 248 52.5% male 248 patients (117 female, 130 male) Inclusion criteria: adult patients with bloodstream infections caused by Enterobacterales and having undergone appropriate source control Key exclusion criteria: pregnancy, uncontrolled source of bacteremia at inclusion or in the following 24 hours, post-chemotherapy neutropenia expected to persist > 7 days, bacteremia secondary to infections requiring prolonged antibiotic therapy Interventions N=119 7-day course (standard antibiotic treatment approved for Enterobacteriaceae infections for a period of 7 days) https://web.pathway.md/studies/recxIrZA8ZEHbSYmI 1/2 6/29/23, 11:42 PM SHORTEN Pathway N=129 14-day course (standard antibiotic treatment approved for Enterobacteriaceae infections for a period of 14 days) Primary outcome Days of antibiotic treatment at end of follow-up 14.0 days 14 10.5 days 7.0 days 7 3.5 days Significant increase 0.0 days 7-day course 14-day course Significant increase in days of antibiotic treatment at the end of follow-up (7 days vs. 14 days; AD 7 days, 95% CI 7 to -7) Secondary outcomes No significant difference in absence of clinical cure (7.3% vs. 9.8%; ARD -2.6, 95% CI -10 to 5.1) No significant difference in relapse of bloodstream infection (6.5% vs. 5%; ARD 1.5, 95% CI -4.8 to 8.4) No significant difference in relapse of fever (19.1% vs. 19.3%; ARD -0.2, 95% CI -10.4 to 10.1) Safety outcomes No significant differences in severe adverse events, drug-related reactions. Conclusion In adult patients with bloodstream infections caused by Enterobacterales and having undergone appropriate source control, 7-day course was superior to 14-day course with respect to days of antibiotic treatment at the end of follow-up. Reference Jos Molina, Enrique Montero-Mateos, Julia Praena-Segovia et al. Seven-versus 14-day course of antibiotics for the treatment of bloodstream infections by Enterobacterales: a randomized, controlled trial. Clin Microbiol Infect. 2022 Apr;28(4):550-557. Open reference URL https://web.pathway.md/studies/recxIrZA8ZEHbSYmI 2/2

6/29/23, 11:57 PM Simon Pathway Feedback Search Clinical Topics Home Studies Simon Simon Trial question What is the role of a high-flow nasal cannula for preoxygenation before intubation in patients with hypoxemic respiratory failure? Study design Single center Open label RCT Population Characteristics of study participants 45.0% female N = 40 55.0% male 40 patients (18 female, 22 male) Inclusion criteria: critically ill subjects with hypoxemic respiratory failure Key exclusion criteria: blocked nasopharynx, contraindications for nose-mouth mask or high flow nasal cannula oxygen, expected difficult airway, emergency endotracheal intubation Interventions N=20 high-flow nasal cannula (an Optiflow system for preoxygenation with oxygen flow set to 50 L/min) N=20 bag-valve-mask (AMBU SPUR II disposable resuscitator for preoxygenation with oxygen flow set at 10 L/min) Primary outcome Mean lowest oxygen saturation during intubation 89.0 % 89 86 66.8 % 44.5 % https://web.pathway.md/studies/rec2L2Dg0NqIwnJHl 1/2 6/29/23, 11:57 PM Simon Pathway 22.3 % No significant difference 0.0 % High-flow nasal cannula Bag-valve-mask No significant difference in mean lowest oxygen saturation during intubation (89% vs. 86%; AD 3%, 95% CI -6.8 to 12.8) Secondary outcomes No significant difference in mean duration of intubation (30 s vs. 37 s; AD -7 s, 95% CI -21.51 to 7.51) No significant difference in abortion of apnea phase and emergency intubation due to progressive hypoxemia (10% vs. 5%; AD 5%, 95% CI -10.95 to 20.95) Safety outcomes No significant differences in time points before and after intubation concerning oxygen saturation, the ratio of the partial pressure of oxygen and FiO2, and partial pressure of CO2. Conclusion In critically ill subjects with hypoxemic respiratory failure, high-flow nasal cannula was not superior to bag-valve-mask with respect to mean lowest oxygen saturation during intubation. Reference Marcel Simon, Christian Wachs, Stephan Braune et al. High-Flow Nasal Cannula Versus Bag-Valve- Mask for Preoxygenation Before Intubation in Subjects With Hypoxemic Respiratory Failure. Respir Care. 2016 Sep;61(9):1160-7. Open reference URL https://web.pathway.md/studies/rec2L2Dg0NqIwnJHl 2/2

6/29/23, 11:42 PM SIREN-C3PO Pathway Feedback Search Clinical Topics Home Studies SIREN C3PO SIREN C3PO Disease COVID 19 infection Trial question What is the role of early convalescent plasma in high-risk outpatients with COVID-19? Study design Multi-center Single blinded RCT Population Characteristics of study participants 54.0% female N = 511 46.0% male 511 patients (274 female, 237 male) Inclusion criteria: patients who were being treated in an emergency department for COVID-19 symptoms Key exclusion criteria: receipt of another investigational treatment for COVID-19; patients ineligible to receive up to 250 ml of fluid; prior adverse reaction from blood product transfusion; receipt of any blood product within the past 120 days Interventions N=257 convalescent plasma (1 unit of convalescent plasma with a high titer of antibodies against SARS-CoV-2) N=254 placebo (1 unit of saline with multivitamin) https://web.pathway.md/studies/recXSYYyWmQUskP17 1/2 6/29/23, 11:42 PM SIREN-C3PO Pathway Primary outcome Rate of disease progression within 15 days 31.9 % 31.9 30 23.9 % 15.9 % 8.0 % No significant difference 0.0 % Convalescent plasma Placebo No significant difference in the rate of disease progression within 15 days (30% vs. 31.9%; ARD -1.9, 95% CI -9.8 to 6) Secondary outcomes No significant difference in the rate of death with 30 days (1.9% vs. 0.4%; AD 1.6%, 95% CI -0.5 to 4.2) No significant difference in hospital-free days (28.3 days vs. 28.6 days; MD -0.3, 95% CI -1.1 to 0.4) No significant difference in worsening of symptoms based on the 5-category outpatient scale (41.6% vs. 45.7%; HR 0.9, 95% CI 0.69 to 1.17) Safety outcomes No significant difference in other adverse events. Significant differences in dyspnea (2.3% vs. 6.7%), infusion related reaction (5.8% vs. 0.4%). Conclusion In patients who were being treated in an emergency department for COVID-19 symptoms, convalescent plasma was not superior to placebo with respect to the rate of disease progression within 15 days. Reference Frederick K Korley, Valerie Durkalski-Mauldin, Sharon D Yeatts et al. Early Convalescent Plasma for High-Risk Outpatients with Covid-19. N Engl J Med. 2021 Nov 18;385(21):1951-1960. Open reference URL https://web.pathway.md/studies/recXSYYyWmQUskP17 2/2

6/29/23, 11:42 PM SKY-DEX Pathway Feedback Search Clinical Topics Home Studies SKY DEX SKY DEX Trial question What is the role of low-dose nocturnal dexmedetomidine in critically ill adults during ICU stay? Study design Multi-center Double blinded RCT Population Characteristics of study participants 36.0% female N = 100 64.0% male 100 patients (36 female, 64 male) Inclusion criteria: delirium-free critically ill adults receiving sedatives Key exclusion criteria: presence of delirium, history of irreversible brain disease consistent with severe dementia, admitted with a primary neurologic condition or injury, acute alcohol withdrawal requiring benzodiazepine administration, history of hepatic encephalopathy or end-stage liver disease, current treatment with dexmedetomidine or clonidine, expected death within 24 hours Interventions N=50 nocturnal dexmedetomidine (intravenous dose of 0.2 g/kg/hour, titrated by 0.1 g/kg/hour every 15 minutes until a goal Richmond Agitation and Sedation Scale score of -1 or maximum rate of 0.7 g/kg/hour reached) N=50 placebo (equivalent mL/hour of the placebo until ICU discharge) Primary outcome Delirium-free during intensive care unit stay 80.0 % 80 60.0 % 54 https://web.pathway.md/studies/recVe3VLZTJy2mhcf 1/2 6/29/23, 11:42 PM SKY-DEX Pathway 40.0 % Significant decrease 20.0 % NNH = 4 0.0 % Nocturnal dexmedetomidine Placebo Significant decrease in delirium-free during the ICU stay (80% vs. 54%; RR 0.44, 95% CI 0.23 to 0.82) Secondary outcomes Significant increase in days free of delirium in the ICU (8 days vs. 6 days; AD 2 days, 95% CI 0.81 to 3.19) Significant increase in Leeds Sleep Evaluation Questionnaire score (10 vs. 10; AD 0.02, 95% CI 0.42 to 1.92) Significant decrease in the rate of total proportion of days spent with coma (12% vs. 19%; RR 0.63, 95% CI 0.26 to 1) Safety outcomes No significant differences in hypotension, bradycardia, death in the hospital. Significant difference in severe pain (40% vs. 66%). Conclusion In delirium-free critically ill adults receiving sedatives, nocturnal dexmedetomidine was superior to placebo with respect to a delirium-free during the ICU stay. Reference Yoanna Skrobik, Matthew S Duprey, Nicholas S Hill et al. Low-Dose Nocturnal Dexmedetomidine Prevents ICU Delirium. A Randomized, Placebo-controlled Trial. Am J Respir Crit Care Med. 2018 May 1;197(9):1147-1156. Open reference URL https://web.pathway.md/studies/recVe3VLZTJy2mhcf 2/2

6/29/23, 11:44 PM SMART Pathway Feedback Search Clinical Topics Home Studies SMART SMART Disease Asthma Trial question What is the effect of salmeterol plus usual pharmacotherapy in patients with asthma? Study design Multi-center Double blinded RCT Population Characteristics of study participants 63.6% female N = 26355 36.4% male 26355 patients (16671 female, 9389 male) Inclusion criteria: patients > 12 years of age with asthma Key exclusion criteria: pregnancy, high-risk significant systemic disease, history of adverse reaction to sympathomimetic amine drug, or current use of -blockers Interventions N=13176 salmeterol (42 g twice a day via metered-dose inhaler plus usual pharmacotherapy) N=13179 placebo (placebo metered-dose inhaler twice a day plus usual pharmacotherapy) Primary outcome Respiratory-related deaths or life-threatening experiences 0.4 % 0.38 https://web.pathway.md/studies/recUEYCHv4bQz51DH 1/2 6/29/23, 11:44 PM SMART Pathway 0 38 0.3 % 0.27 0.2 % 0.1 % No significant difference 0.0 % Salmeterol Placebo No significant difference in respiratory-related deaths or life-threatening experiences (0.38% vs. 0.27%; RR 1.4, 95% CI 0.91 to 2.14) Secondary outcomes Borderline significant increase in respiratory-related deaths (0.18% vs. 0.08%; RR 2.16, 95% CI 1.06 to 4.41) Borderline significant increase in asthma-related deaths (0.1% vs. 0.02%; RR 4.37, 95% CI 1.25 to 15.34) Borderline significant increase in asthma-related death or life-threatening experiences (0.28% vs. 0.17%; RR 1.71, 95% CI 1.01 to 2.89) Safety outcomes No significant difference in serious adverse events. Significant difference in survival rate in relation to time to the first serious adverse event causing discontinuation (95.61% vs. 96.18%). Conclusion In patients > 12 years of age with asthma, salmeterol was not superior to placebo with respect to a respiratory-related deaths or life-threatening experiences. Reference Nelson HS, Weiss ST, Bleecker ER et al. The Salmeterol Multicenter Asthma Research Trial: a comparison of usual pharmacotherapy for asthma or usual pharmacotherapy plus salmeterol. Chest. 2006 Jan;129(1):15-26. Open reference URL https://web.pathway.md/studies/recUEYCHv4bQz51DH 2/2

6/29/23, 11:44 PM SMART-CHOICE (1-year follow-up) Pathway Feedback Search Clinical Topics Home Studies SMART CHOICE 1-year follow-up) SMART CHOICE 1-year follow-up) Disease Disease Disease Coronary artery disease Non-ST-elevation myocardial inf ST-elevat Trial question Is P2Y12 inhibitor monotherapy noninferior to dual antiplatelet therapy in patients undergoing PCI? Study design Multi-center Open label RCT Population Characteristics of study participants 27.0% female N = 2993 73.0% male 2993 patients (795 female, 2198 male) Inclusion criteria: patients undergoing PCI with drug-eluting stents Key exclusion criteria: known hypersensitivity or contraindication to aspirin; clopidogrel; prasugrel; ticagrelor; everolimus or sirolimus Interventions N=1495 P2Y12 inhibitor monotherapy (aspirin plus a P2Y12 inhibitor for 3 months and thereafter a P2Y12 inhibitor alone) N=1498 dual antiplatelet therapy (aspirin plus a P2Y12 inhibitor for at least 12 months) Primary outcome Major adverse cardiac and cerebrovascular events at 12 months https://web.pathway.md/studies/recIYgx9u5z45VrEl 1/2 6/29/23, 11:44 PM SMART-CHOICE (1-year follow-up) Pathway 2.9 % 2.9 2.5 2.2 % 1.4 % Difference not exceeding nonferiority margin 0.7 % 0.0 % P2Y12 inhibitor monotherapy Dual antiplatelet therapy Difference not exceeding nonferiority margin in major adverse cardiac and cerebrovascular events at 12 months (2.9% vs. 2.5%; AD 0.4%, 95% CI -Infinity to 1.3) Secondary outcomes No significant difference in death from all causes (1.4% vs. 1.2%; HR 1.18, 95% CI 0.63 to 2.21) No significant difference in myocardial infarction (0.8% vs. 1.2%; HR 0.66, 95% CI 0.31 to 1.4) No significant difference in stroke (0.8% vs. 0.3%; HR 2.23, 95% CI 0.78 to 6.43) Safety outcomes No significant difference in major bleeding. Significant difference in bleeding (2.0% vs. 3.4%). Conclusion In patients undergoing PCI with drug-eluting stents, P2Y12 inhibitor monotherapy was noninferior to dual antiplatelet therapy with respect to major adverse cardiac and cerebrovascular events at 12 months. Reference Joo-Yong Hahn, Young Bin Song, Ju-Hyeon Oh et al. Effect of P2Y12 Inhibitor Monotherapy vs Dual Antiplatelet Therapy on Cardiovascular Events in Patients Undergoing Percutaneous Coronary Intervention: The SMART-CHOICE Randomized Clinical Trial. JAMA. 2019 Jun 25;321(24):2428- 2437. Open reference URL https://web.pathway.md/studies/recIYgx9u5z45VrEl 2/2

6/29/23, 11:44 PM SMART-CHOICE (3-year follow-up) Pathway Feedback Search Clinical Topics Home Studies SMART CHOICE 3-year follow-up) SMART CHOICE 3-year follow-up) Disease Disease Disease Coronary artery disease Non-ST-elevation myocardial inf ST-elevat Trial question Is P2Y12 inhibitor monotherapy after short-term dual antiplatelet therapy noninferior to long-term dual antiplatelet therapy after PCI? Study design Multi-center Open label RCT Population Characteristics of study participants 27.0% female N = 2993 73.0% male 2993 patients (795 female, 2198 male) Inclusion criteria: patients who underwent PCI with drug-eluting stent Key exclusion criteria: hemodynamic instability or cardiogenic shock; active bleeding; hypersensitivity/contraindication to study medications; pregnancy; noncardiac comorbid conditions with life expectancy < 2 years Interventions N=1495 P2Y12 inhibitor monotherapy (P2Y12 inhibitor monotherapy after 3 months of dual antiplatelet therapy) N=1498 prolonged dual antiplatelet therapy (extended use of dual antiplatelet therapy up to 36 months) https://web.pathway.md/studies/recRbsOf0R882zuuW 1/2 6/29/23, 11:44 PM SMART-CHOICE (3-year follow-up) Pathway Primary outcome Major adverse cardiac and cerebrovascular events at 3 years 6.3 % 6.3 6.1 4.7 % 3.1 % Difference not exceeding nonferiority margin 1.6 % 0.0 % P2Y12 inhibitor monotherapy Prolonged dual antiplatelet therapy Difference not exceeding nonferiority margin in major adverse cardiac and cerebrovascular events at 3 years (6.3% vs. 6.1%; HR 1.06, 95% CI 0.79 to 1.44) Secondary outcomes Significant decrease in bleeding (3.2% vs. 8.2%; HR 0.39, 95% CI 0.28 to 0.55) Significant decrease in major bleeding (1.2% vs. 2.4%; HR 0.56, 95% CI 0.31 to 0.99) No significant difference in cardiac death (2.2% vs. 2%; HR 1.12, 95% CI 0.68 to 1.89) Conclusion In patients who underwent PCI with drug-eluting stent, P2Y12 inhibitor monotherapy was noninferior to prolonged dual antiplatelet therapy with respect to major adverse cardiac and cerebrovascular events at 3 years. Reference Ki Hong Choi, Yong Hwan Park, Young Bin Song et al. Long-term Effects of P2Y12 Inhibitor Monotherapy After Percutaneous Coronary Intervention: 3-Year Follow-up of the SMART-CHOICE Randomized Clinical Trial. JAMA Cardiol. 2022 Nov 1;7(11):1100-1108. Open reference URL https://web.pathway.md/studies/recRbsOf0R882zuuW 2/2

6/29/23, 11:44 PM SMART-MED and SMART-SURG Pathway Feedback Search Clinical Topics Home Studies SMART MED and SMART SURG SMART MED and SMART SURG Disease Disease Sepsis and septic shock Traumatic brain injury Trial question What is the effect of balanced crystalloids for intravenous fluid administration in critically ill adult patients? Study design Multi-center Open label RCT Population Characteristics of study participants 42.0% female N = 15802 58.0% male 15802 patients (6705 female, 9097 male) Inclusion criteria: critically ill adult patients requiring intravenous fluid administration Key exclusion criteria: age < 18 years old Interventions N=7942 balanced crystalloids (either lactated Ringer's solution or Plasma-Lyte A) N=7860 saline (0.9% sodium chloride) Primary outcome Rate of major adverse kidney event within 30 days 15.4 15 4 % 14 3 https://web.pathway.md/studies/recHwhXTuRTcpTO6t 1/2 6/29/23, 11:44 PM 15.4 % SMART-MED and SMART-SURG Pathway 5 14.3 11.6 % 7.7 % Significant decrease 3.9 % NNT = 91 0.0 % Balanced crystalloids Saline Significant decrease in the rate of major adverse kidney event within 30 days (14.3% vs. 15.4%; aOR 0.9, 95% CI 0.82 to 0.99) Secondary outcomes No significant difference in new RRT (2.5% vs. 2.9%; aOR 0.84, 95% CI 0.68 to 1.02) No significant difference in persistent renal dysfunction (6.4% vs. 6.6%; aOR 0.96, 96% CI 0.84 to 1.1) Safety outcomes No significant differences in change in creatinine levels, death in the hospital before 60 days. Conclusion In critically ill adult patients requiring intravenous fluid administration, balanced crystalloids were superior to saline with respect to the rate of major adverse kidney event within 30 days. Reference Semler MW, Self WH, Wanderer JP et al. Balanced Crystalloids versus Saline in Critically Ill Adults. N Engl J Med. 2018 Mar 1;378(9):829-839. Open reference URL https://web.pathway.md/studies/recHwhXTuRTcpTO6t 2/2

6/29/23, 11:44 PM SOAP II Pathway Feedback Search Clinical Topics Home Studies SOAP II SOAP II Disease Sepsis and septic shock Trial question What is the role of dopamine as first-line vasopressor agent in patients with shock? Study design Multi-center Double blinded RCT Population Characteristics of study participants 43.0% female N = 1679 57.0% male 1679 patients (723 female, 956 male) Inclusion criteria: patients with shock Key exclusion criteria: age < 18 years; already received a vasopressor agent (dopamine, norepinephrine, epinephrine, or phenylephrine) for > 4 hours during the current episode of shock; serious arrhythmia, such as rapid AF (> 160 beats/min) or VT; or declared brain-dead Interventions N=858 dopamine (dose determined according to the patient's body weight, could be increased or decreased by 2 g/kg/min) N=821 norepinephrine (dose determined according to the patient's body weight, could be increased or decreased by 0.02 g/kg/min) https://web.pathway.md/studies/recScwrf3pouG7jpl 1/2 6/29/23, 11:44 PM SOAP II Pathway Primary outcome Death at 28 days 52.5 % 52.5 48.5 39.4 % 26.3 % 13.1 % No significant difference 0.0 % Dopamine Norepinephrine No significant difference in death at 28 days (52.5% vs. 48.5%; OR 1.17, 95% CI 0.97 to 1.42) Secondary outcomes Significant increase in required open-label norepinephrine therapy (26% vs. 20%; RR 1.3, 95% CI 0.53 to 2.07) Significant increase in open-label vasopressors not needed (12.6 vs. 14.2; MD 1.6, 95% CI 0.44 to 2.76) Safety outcomes Significant differences in arrhythmic events (24.1% vs. 12.4%, p < 0.001). Conclusion In patients with shock, dopamine was not superior to norepinephrine with respect to death at 28 days. Reference De Backer D, Biston P, Devriendt J et al. Comparison of dopamine and norepinephrine in the treatment of shock. N Engl J Med. 2010 Mar 4;362(9):779-89. Open reference URL https://web.pathway.md/studies/recScwrf3pouG7jpl 2/2

6/29/23, 11:45 PM SOCRATES Pathway Feedback Search Clinical Topics Home Studies SOCRATES SOCRATES Disease Disease Acute ischemic stroke Transient ischemic attack Trial question What is the effect of ticagrelor in patients with acute ischemic stroke or TIA? Study design Multi-center Double blinded RCT Population Characteristics of study participants 42.0% female N = 13199 58.0% male 13199 patients (5483 female, 7716 male) Inclusion criteria: patients with nonsevere ischemic stroke or high-risk TIA who had not received intravenous or intraarterial thrombolysis and were not considered to have ha a cardioembolic stroke Key exclusion criteria: specific antiplatelet therapy or anticoagulation therapy was planned or if carotid, cerebrovascular, or coronary revascularization was planned that would require halting study treatment within 7 days after randomization; hypersensitivity to ticagrelor or aspirin; history of AF, ventricular aneurysm, or suspicion of cardioembolic cause for TIA or stroke; underwent intravenous or intraarterial thrombolysis or mechanical thrombectomy within 24 hours before randomization Interventions https://web.pathway.md/studies/rec3J5Si17H1GrXYC 1/2 6/29/23, 11:45 PM SOCRATES Pathway N=6589 ticagrelor (180 mg loading dose on day 1 followed by 90 mg BID for days 2 through 90) N=6610 aspirin (300 mg on day 1 followed by 100 mg daily for days 2 through 90) Primary outcome Time to occurrence of stroke, myocardial infarction, or death at 90 days 7.5 % 7.5 6.7 5.6 % 3.8 % 1.9 % No significant difference 0.0 % Ticagrelor Aspirin No significant difference in time to occurrence of stroke, myocardial infarction, or death at 90 days (6.7% vs. 7.5%; HR 0.89, 95% CI 0.78 to 1.01) Secondary outcomes Borderline significant decrease in ischemic stroke (5.8% vs. 6.7%; HR 0.87, 95% CI 0.76 to 1) Safety outcomes No significant differences in major bleeding (0.5% vs. 0.6%), intracranial hemorrhage (0.2% vs. 0.3%), and fatal bleeding (0.1% vs. 0.1%). Conclusion In patients with nonsevere ischemic stroke or high-risk TIA who had not received intravenous or intraarterial thrombolysis and were not considered to have ha a cardioembolic stroke, ticagrelor was not superior to aspirin with respect to time to occurrence of stroke, myocardial infarction, or death at 90 days. Reference Johnston SC, Amarenco P, Albers GW et al. Ticagrelor versus Aspirin in Acute Stroke or Transient Ischemic Attack. N Engl J Med. 2016 Jul 7;375(1):35-43. Open reference URL https://web.pathway.md/studies/rec3J5Si17H1GrXYC 2/2

6/29/23, 11:44 PM SODIUM-HF Pathway Feedback Search Clinical Topics Home Studies SODIUM HF SODIUM HF Disease Heart failure Trial question What is the role of dietary intervention to reduce sodium intake in patients with HF? Study design Multi-center Open label RCT Population Characteristics of study participants 33.0% female N = 806 67.0% male 806 patients (268 female, 538 male) Inclusion criteria: adult patients with chronic HF receiving optimally tolerated medical treatment Key exclusion criteria: average dietary intake of sodium < 1500 mg/day; serum sodium < 130 mmol/L; renal failure; hepatic failure; uncontrolled thyroid disorder; uncontrolled AF; hospitalization due to cardiovascular causes in the previous month Interventions N=397 reduced sodium intake (sodium intake < 1500 mg/day) N=409 usual sodium intake (usual care according to local guidelines) Primary outcome https://web.pathway.md/studies/recNj64shxbvZamVm 1/2 6/29/23, 11:44 PM SODIUM-HF Pathway A composite of admission to hospital for cardiovascular causes, emergency department visit for cardiovascular causes, or death from all causes at 12 months 17.0 % 17 15 12.8 % 8.5 % 4.3 % No significant difference 0.0 % Reduced sodium intake Usual sodium intake No significant difference in a composite of admission to hospital for cardiovascular causes, emergency department visit for cardiovascular causes, or death from all causes at 12 months (15% vs. 17%; HR 0.89, 95% CI 0.63 to 1.26) Secondary outcomes No significant difference in death from all causes (6% vs. 4%; HR 1.38, 95% CI 0.73 to 2.6) No significant difference in hospitalization for cardiovascular causes (10% vs. 12%; HR 0.82, 95% CI 0.54 to 1.24) No significant difference in cardiovascular-related emergency department visits (4% vs. 4%; HR 1.21, 95% CI 0.6 to 2.41) Conclusion In adult patients with chronic HF receiving optimally tolerated medical treatment, reduced sodium intake was not superior to usual sodium intake with respect to a composite of admission to hospital for cardiovascular causes, emergency department visit for cardiovascular causes, or death from all causes at 12 months. Reference Justin A Ezekowitz, Eloisa Colin-Ramirez, Heather Ross et al. Reduction of dietary sodium to less than 100 mmol in heart failure (SODIUM-HF): an international, open-label, randomised, controlled trial. Lancet. 2022 Apr 9;399(10333):1391-1400. Open reference URL https://web.pathway.md/studies/recNj64shxbvZamVm 2/2

6/29/23, 11:57 PM Solidarity (remdesivir) Pathway Feedback Search Clinical Topics Home Studies Solidarity (remdesivir) Solidarity (remdesivir) Disease COVID 19 infection Trial question What is the role of remdesivir in patients hospitalized with COVID-19? Study design Multi-center Open label RCT Population Characteristics of study participants 37.0% female N = 8275 63.0% male 8275 patients (3035 female, 5240 male) Inclusion criteria: adult patients hospitalized with COVID-19 Key exclusion criteria: serious chronic liver; heart disease; pregnancy Interventions N=4146 remdesivir (10 daily infusions unless discharged earlier) N=4129 no remdesivir (standard of care alone) Primary outcome In-hospital mortality 15.6 % 15.6 14.5 https://web.pathway.md/studies/recRqmfTo4ZnEUlbY 1/2 6/29/23, 11:57 PM Solidarity (remdesivir) Pathway 11.7 % 7.8 % 3.9 % No significant difference 0.0 % Remdesivir No remdesivir No significant difference in in-hospital mortality (14.5% vs. 15.6%; RR 0.91, 95% CI 0.82 to 1.02) Secondary outcomes Significant decrease in progression to ventilation (14.1% vs. 15.7%; RR 0.88, 95% CI 0.77 to 1) Significant decrease in death or progression to ventilation (19.6% vs. 22.5%; RR 0.84, 95% CI 0.75 to 0.93) Conclusion In adult patients hospitalized with COVID-19, remdesivir was not superior to no remdesivir with respect to a in-hospital mortality. Reference WHO Solidarity Trial Consortium. Remdesivir and three other drugs for hospitalised patients with COVID-19: final results of the WHO Solidarity randomised trial and updated meta-analyses. Lancet. 2022 May 21;399(10339):1941-1953. Open reference URL https://web.pathway.md/studies/recRqmfTo4ZnEUlbY 2/2

6/29/23, 11:44 PM SOLSTICE Pathway Feedback Search Clinical Topics Home Studies SOLSTICE SOLSTICE Disease Disease Kidney transplantation Liver transplantation Trial question Is maribavir superior to investigator-assigned therapy in patients with refractory CMV infections post-transplant? Study design Multi-center Open label RCT Population Characteristics of study participants 39.0% female N = 352 61.0% male 352 patients (139 female, 213 male) Inclusion criteria: hematopoietic-cell and solid-organ transplant recipients with refractory CMV infections Key exclusion criteria: resistant or refractory CMV infection due to inadequate adherence to prior anti-CMV treatment; CMV disease with CNS involvement or retinitis; the concomitant need for leflunomide, letermovir, or artesunate Interventions N=235 maribavir (400 mg BID for 8 weeks, with 12 weeks follow-up) N=117 investigator-assigned therapy (mono or combination therapy with valganciclovir/ganciclovir, foscarnet, or cidofovir for 8 weeks, with 12 weeks follow-up) https://web.pathway.md/studies/reclDfnUMo1nx0NN8 1/2 6/29/23, 11:44 PM SOLSTICE Pathway Primary outcome Rate of confirmed cytomegalovirus clearance at end of week 8 55.7 % 55.7 41.8 % 27.9 % 23.9 Significant increase 13.9 % NNH = 3 0.0 % Maribavir Investigator-assigned therapy Significant increase in the rate of confirmed CMV clearance at end of week 8 (55.7% vs. 23.9%; AD 32.8%, 95% CI 22.8 to 42.74) Secondary outcomes Significant increase in the rate of CMV clearance and symptom control at end of week 8, maintained through week 16 (18.7% vs. 10.3%; AD 9.5%, 95% CI 2.02 to 16.88) Significant increase in the rate of CMV clearance at end of week 12 (22.6% vs. 10.3%; AD 13.5%, 95% CI 5.84 to 21.17) Significant increase in the rate of CMV clearance at end of week 20 (18.3% vs. 9.4%; AD 9.8%, 95% CI 2.58 to 17.06) Safety outcomes No significant difference in any adverse events. Significant differences in dysgeusia (37.2% vs. 3.4%), AKI (8.5% vs. 21.3% in foscarnet), neutropenia (9.4% vs. 33.9% in valganciclovir/ganciclovir). Conclusion In hematopoietic-cell and solid-organ transplant recipients with refractory CMV infections, maribavir was superior to investigator-assigned therapy with respect to the rate of confirmed CMV clearance at end of week 8. Reference Robin K Avery, Sophie Alain, Barbara D Alexander et al. Maribavir for Refractory Cytomegalovirus Infections With or Without Resistance Post-Transplant: Results from a Phase 3 Randomized Clinical Trial. Clin Infect Dis. 2021 Dec 2;ciab988. Open reference URL https://web.pathway.md/studies/reclDfnUMo1nx0NN8 2/2

6/29/23, 11:44 PM SOLSTICE Pathway Feedback Search Clinical Topics Home Studies SOLSTICE SOLSTICE Disease Disease Colon cancer Rectal cancer Trial question Is first-line trifluridine-tipiracil plus bevacizumab superior to capecitabine plus bevacizumab in patients with metastatic colorectal cancer ineligible for intensive therapy? Study design Multi-center Open label RCT Population Characteristics of study participants 46.0% female N = 856 54.0% male 856 patients (394 female, 462 male) Inclusion criteria: adult patients with histologically confirmed metastatic colorectal cancer, ineligible for full-dose doublet or triplet chemotherapy and curative resection Key exclusion criteria: pregnancy; symptomatic CNS metastases; major surgery within 4 weeks prior to randomization; allergy/contraindication to study drugs Interventions N=426 trifluridine-tipiracil plus bevacizumab (oral trifluridine-tipiracil 35 mg/m BID on days 1-5 and 8-12 plus 5 mg/kg bevacizumab IV on days 1 and 15 of each 28-day cycle) N=430 capecitabine plus bevacizumab (oral capecitabine 1,250 mg/m BID on days 1-15 of each cycle plus 7.5 mg/kg intravenous bevacizumab on day 1 of each 21-day cycle) https://web.pathway.md/studies/recYJJ7lhghVTCAKZ 1/2 6/29/23, 11:45 PM SOLSTICE Pathway Primary outcome Progression-free survival 9.4 months 9.4 9.3 7.1 months 4.7 months 2.4 months No significant difference 0.0 months Trifluridine-tipiracil plus bevacizumab Capecitabine plus bevacizumab No significant difference in progression-free survival (9.4 months vs. 9.3 months; HR 0.87, 95% CI 0.75 to 1.02) Secondary outcomes No significant difference in overall response rate (36% vs. 42%; RR 0.86, 95% CI -0.14 to 1.86) No significant difference in disease control rates (86% vs. 85%; RR 1.01, 95% CI -2.9 to 4.92) Safety outcomes No significant difference in treatment-related deaths. Significant differences in grade 3 treatment-emergent adverse events (52% vs. 1%), decreased neutrophil count (18% vs. < 1%), anemia (14% vs. 4%), hand-foot syndrome (0% vs. 15%). Conclusion In adult patients with histologically confirmed metastatic colorectal cancer, ineligible for full-dose doublet or triplet chemotherapy and curative resection, trifluridine-tipiracil plus bevacizumab was not superior to capecitabine plus bevacizumab with respect to a progression-free survival. Reference Thierry Andr , Alfredo Falcone, Yaroslav Shparyk et al. Trifluridine-tipiracil plus bevacizumab versus capecitabine plus bevacizumab as first-line treatment for patients with metastatic colorectal cancer ineligible for intensive therapy (SOLSTICE): a randomised, open-label phase 3 study. Lancet Gastroenterol Hepatol. 2023 Feb;8(2):133-144. Open reference URL https://web.pathway.md/studies/recYJJ7lhghVTCAKZ 2/2

6/29/23, 11:44 PM SOLVD Pathway Feedback Search Clinical Topics Home Studies SOLVD SOLVD Disease Heart failure Trial question What is the role of enalapril in patients with HF with a reduced ejection fraction? Study design Multi-center Double blinded RCT Population Characteristics of study participants 20.0% female N = 2569 80.0% male 2569 patients (504 female, 2065 male) Inclusion criteria: patients with HF with a reduced ejection fraction and receiving conventional treatment Key exclusion criteria: age > 80 years, hemodynamically serious valvular disease requiring surgery, unstable angina pectoris, myocardial infarction during the previous month, severe pulmonary disease, or serum creatinine level > 177 mcmol/L Interventions N=1285 enalapril (at doses of 2.5 to 20 mg/day) N=1284 placebo (matching placebo daily) Primary outcome https://web.pathway.md/studies/recJ25hKBJYcXzRhW 1/2 6/29/23, 11:45 PM SOLVD Pathway Death 39.7 % 39.7 35.2 29.8 % 19.9 % Significant increase 9.9 % NNH = 22 0.0 % Enalapril Placebo Significant increase in death (35.2% vs. 39.7%; RR 16, 95% CI 5 to 26) Secondary outcomes Significant increase in death or hospitalization for worsening HF (47.7% vs. 57.3%; RR 26, 95% CI 18 to 34) Conclusion In patients with HF with a reduced ejection fraction and receiving conventional treatment, enalapril was superior to placebo with respect to death. Reference SOLVD Investigators, Yusuf S, Pitt B et al. Effect of enalapril on survival in patients with reduced left ventricular ejection fractions and congestive heart failure. N Engl J Med. 1991 Aug 1;325(5):293- 302. Open reference URL https://web.pathway.md/studies/recJ25hKBJYcXzRhW 2/2

6/29/23, 11:57 PM SoM Pathway Feedback Search Clinical Topics Home Studies SoM SoM Disease Antimicrobial-resistant Gram-ne Trial question Is the isolation strategy of contact precautions in a multiple-bed room noninferior to a strategy of contact precautions in a single-bed room for patients with extended-spectrum -lactamase- producing Enterobacteriaceae? Study design Multi-center Open label RCT Population Characteristics of study participants 45.4% female N = 10220 54.6% male 10220 patients (4532 female, 5452 male) Inclusion criteria: adult patients with extended-spectrum -lactamase-producing Enterobacteriaceae cultured from a routine clinical sample Key exclusion criteria: age < 18 years, a strict indication for barrier precautions in a single-bed room, no culture result reported within 7 days after the culture was obtained or before discharge, a wardmate known to be colonized or infected with an ESBL-producing Enterobacteriaceae isolate of the same bacterial species with a similar antibiogram Interventions https://web.pathway.md/studies/recEZwZylaRgLSO5q 1/2 6/29/23, 11:57 PM SoM Pathway N=304 + 4578 a multiple-bed room isolation strategy (contact precautions in a multiple-bed room consisting of index patients plus wardmates) N=312 + 4790 a single-bed room isolation strategy (contact precautions in a single-bed room with index patients plus wardmates) Primary outcome Transmission of extended-spectrum -lactamase-producing Enterobacteriaceae to at least one wardmate 7.0 % 7 5.3 % 4 3.5 % Difference not exceeding nonferiority margin 1.8 % 0.0 % A multiple-bed room isolation strategy A single-bed room isolation strategy Difference not exceeding nonferiority margin in transmission of extended-spectrum -lactamase- producing Enterobacteriaceae to at least one wardmate (7% vs. 4%; ARD 3.4, 90% CI -0.3 to 7.1) Secondary outcomes No significant difference in rectal carriage of ESBL-producing Enterobacteriaceae in all wardmates (9% vs. 8%; RR 1.14, 95% CI 0.97 to 1.33) No significant difference in length of hospital stay in wardmates (11 days vs. 11 days; RR 1.02, 95% CI 0.96 to 1.08) No significant difference in death at 30 days in wardmates (4% vs. 4%; RR 1.14, 95% CI 0.9 to 1.43) Conclusion In adult patients with extended-spectrum -lactamase-producing Enterobacteriaceae cultured from a routine clinical sample, a multiple-bed room isolation strategy was noninferior to a single-bed room isolation strategy with respect to transmission of extended-spectrum -lactamase-producing Enterobacteriaceae to at least one wardmate. Reference Marjolein F Q Kluytmans-van den Bergh, Patricia C J Bruijning-Verhagen, Christina M J E Vandenbroucke-Grauls et al. Contact precautions in single-bed or multiple-bed rooms for patients with extended-spectrum -lactamase-producing Enterobacteriaceae in Dutch hospitals: a cluster- randomised, crossover, non-inferiority study. Lancet Infect Dis. 2019 Oct;19(10):1069-1079. Open reference URL https://web.pathway.md/studies/recEZwZylaRgLSO5q 2/2

6/29/23, 11:45 PM SOME Pathway Feedback Search Clinical Topics Home Studies SOME SOME Disease Disease Disease Cancer-associated thrombosis Deep vein thrombosis Pulmonary Trial question What is the role of screening for occult cancer in patients with unprovoked VTE? Study design Multi-center Open label RCT Population Characteristics of study participants 33.0% female N = 854 67.0% male 854 patients (278 female, 576 male) Inclusion criteria: patients who had a first unprovoked VTE Key exclusion criteria: age < 18 years, allergy to contrast media, a CrCl < 60 mL/min, claustrophobia or agoraphobia, a weight > 130 kg, ulcerative colitis, or glaucoma Interventions N=423 limited occult-cancer screening plus CT (basic blood testing, chest radiography, and screening for breast, cervical, and prostate cancer plus comprehensive CT (CT) of the abdomen and pelvis) N=431 limited occult-cancer screening (basic blood testing, chest radiography, and screening for breast, cervical, and prostate cancer) https://web.pathway.md/studies/rec0WZPvAUMQzTWH3 1/2 6/29/23, 11:45 PM SOME Pathway Primary outcome Occult cancer diagnosis at 1 year 4.5 % 4.5 3.4 % 3.2 2.3 % 1.1 % No significant difference 0.0 % Limited occult-cancer screening plus CT Limited occult-cancer screening No significant difference in occult cancer diagnosis at 1 year (4.5% vs. 3.2%; RR 1.4, 95% CI -1.12 to 3.92) Secondary outcomes No significant difference in mean time to a cancer diagnosis (4 vs. 4.2; RR 0.95, 95% CI -10.48 to 12.38) No significant difference in cancer-related death (0.9% vs. 1.4%; RR 0.64, 95% CI -3.1 to 4.38) No significant difference in missed cancer in the primary outcome analysis (26% vs. 29%; RR 0.9, 95% CI -69114.8 to 69116.6) Conclusion In patients who had a first unprovoked VTE, limited occult-cancer screening plus CT was not superior to limited occult-cancer screening with respect to occult cancer diagnosis at 1 year. Reference Carrier M, Lazo-Langner A, Shivakumar S et al. Screening for Occult Cancer in Unprovoked Venous Thromboembolism. N Engl J Med. 2015 Aug 20;373(8):697-704. Open reference URL https://web.pathway.md/studies/rec0WZPvAUMQzTWH3 2/2

6/29/23, 11:45 PM SPARCL Pathway Feedback Search Clinical Topics Home Studies SPARCL SPARCL Disease Disease Disease Acute ischemic stroke Dyslipidemia Transient Trial question What is the role of atorvastatin in patients with recent stroke or TIA and without known coronary heart disease? Study design Multi-center Double blinded RCT Population Characteristics of study participants 40.0% female N = 4731 60.0% male 4731 patients (1908 female, 2823 male) Inclusion criteria: patients with recent stroke or TIA within one to six months, had low-density lipoprotein cholesterol levels of 100 to 190 mg/dL and without known coronary heart disease Key exclusion criteria: AF, other cardiac sources of embolism, and subarachnoid hemorrhage Interventions N=2365 atorvastatin (80 mg/day) N=2366 placebo (matching placebo every day) Primary outcome Fatal or nonfatal stroke https://web.pathway.md/studies/recFONtvShWmHsfq1 1/2 6/29/23, 11:45 PM SPARCL Pathway 13.1 % 13.1 11.2 9.8 % 6.5 % Significant decrease 3.3 % NNT = 53 0.0 % Atorvastatin Placebo Significant decrease in fatal or nonfatal stroke (11.2% vs. 13.1%; HR 0.84, 95% CI 0.71 to 0.99) Secondary outcomes Significant decrease in major cardiovascular events (14.1% vs. 17.2%; HR 0.8, 95% CI 0.69 to 0.92) No significant difference in death from any cause (9.1% vs. 8.9%; HR 1, 95% CI 0.82 to 1.21) Significant decrease in strokes or TIA (15.9% vs. 20.1%; HR 0.77, 95% CI 0.67 to 0.88) Safety outcomes No significant difference in serious adverse events. Significant differences in liver enzymes elevation (2.2% vs. 0.5, p < 0.001). Conclusion In patients with recent stroke or TIA within one to six months, had low-density lipoprotein cholesterol levels of 100 to 190 mg/dL and without known coronary heart disease, atorvastatin was superior to placebo with respect to fatal or nonfatal stroke. Reference Amarenco P, Bogousslavsky J, Callahan A rd et al. High-dose atorvastatin after stroke or transient ischemic attack. N Engl J Med. 2006 Aug 10;355(6):549-59. Open reference URL https://web.pathway.md/studies/recFONtvShWmHsfq1 2/2

6/29/23, 11:45 PM SPICE III Pathway Feedback Search Clinical Topics Home Studies SPICE III SPICE III Trial question What is the role of early sedation with dexmedetomidine among patients undergoing mechanical ventilation in the ICU? Study design Multi-center Open label RCT Population Characteristics of study participants 38.8% female N = 4000 61.2% male 4000 patients (1503 female, 2415 male) Inclusion criteria: critically ill adults who had been undergoing ventilation for < 12 hours in the ICU and were expected to continue to receive ventilatory support for longer than the next calendar day Key exclusion criteria: age under 18 years, invasive ventilation in the ICU for > 12 hours before enrollment, and suspected or proven acute primary brain injury or spinal cord injury Interventions N=1954 dexmedetomidine (starting intravenous dose of 1 g/kg of body weight per hour with a maximum dose of 1.5 g per/kg/hour to achieve a Richmond Agitation Sedation Scale score in the target range) N=1964 usual care (propofol, midazolam, or other sedatives, excluding dexmedetomidine, as directed by the treating physician) Primary outcome Death from any cause at 90 days 29.1 % 29.1 29.1 21.8 % https://web.pathway.md/studies/receTqmAW4SmrZvDj 1/2 6/29/23, 11:45 PM SPICE III Pathway 14.6 % 7.3 % No significant difference 0.0 % Dexmedetomidine Usual care No significant difference in death from any cause at 90 days (29.1% vs. 29.1%; OR 1, 95% CI 0.87 to 1.15) Secondary outcomes No significant difference in death at 180 days (31.5% vs. 31.3%; OR 1.01, 95% CI 0.88 to 1.16) No significant difference in institutional dependency at 180 days (6.7% vs. 7%; OR 0.96, 96% CI 0.73 to 1.27) Significant increase in mean score on short informant questionnaire on cognitive decline in the elderly at 180 days (3.14 vs. 3.08; AD 0.06, 95% CI 0.02 to 0.11) Safety outcomes No significant differences in coma or delirium free days, mean score on the European Quality of Life 5-Dimension 3-Level questionnaire. Significant differences in serious adverse events of bradycardia (0.7% vs. 0.05%), hypotension (0.5% vs. 0.05%), prolonged sinus arrest (0.7% vs. 0.1%). Conclusion In critically ill adults who had been undergoing ventilation for < 12 hours in the ICU and were expected to continue to receive ventilatory support for longer than the next calendar day, dexmedetomidine was not superior to usual care with respect to death from any cause at 90 days. Reference Yahya Shehabi, Belinda D Howe, Rinaldo Bellomo et al. Early Sedation with Dexmedetomidine in Critically Ill Patients. N Engl J Med. 2019 Jun 27;380(26):2506-2517. Open reference URL https://web.pathway.md/studies/receTqmAW4SmrZvDj 2/2

6/29/23, 11:45 PM SPRINT (secondary analysis) Pathway Feedback Search Clinical Topics Home Studies SPRINT (secondary analysis) SPRINT (secondary analysis) Disease Hypertension Trial question What is the long-term effect of intensive BP control in patients with hypertension? Study design Multi-center Open label RCT Population Characteristics of study participants 36.0% female N = 9361 64.0% male 9361 patients (3332 female, 6029 male) Inclusion criteria: patients 50 years of age with hypertension and increased cardiovascular risk Key exclusion criteria: 1 minute standing systolic BP < 110 mgHg; diabetes mellitus; history of stroke; polycystic kidney disease; cardiovascular event/procedure Interventions N=4678 intensive BP control (systolic BP goal < 120 mmHg) N=4683 standard BP control (systolic BP goal < 140 mmHg) Primary outcome Rate of death from cardiovascular causes at a follow-up of 8.8 years 4.3 % 4.28 4.25 https://web.pathway.md/studies/recm7uMmwl1NrbkZk 1/2 6/29/23, 11:45 PM 3 % SPRINT (secondary analysis) Pathway 8 4.25 3.2 % 2.1 % 1.1 % No significant difference 0.0 % Intensive blood pressure control Standard blood pressure control No significant difference in the rate of death from cardiovascular causes at a follow-up of 8.8 years (4.28% vs. 4.25%; HR 1.02, 95% CI 0.84 to 1.24) Secondary outcomes No significant difference in the rate of death from all causes at a follow-up of 8.8 years (13.5% vs. 12.6%; HR 1.08, 95% CI 0.94 to 1.23) Borderline significant decrease in the rate of death from cardiovascular causes at a follow-up of 3.3 years (1.36% vs. 1.96%; HR 0.66, 95% CI 0.49 to 0.89) No significant difference in the rate of death from all causes at a follow-up of 3.3 years (5.2% vs. 6.2%; HR 0.83, 95% CI 0.68 to 1.01) Conclusion In patients 50 years of age with hypertension and increased cardiovascular risk, intensive BP control was not superior to standard BP control with respect to the rate of death from cardiovascular causes at a follow-up of 8.8 years. Reference Byron C Jaeger, Adam P Bress, Joshua D Bundy et al. Longer-Term All-Cause and Cardiovascular Mortality With Intensive Blood Pressure Control: A Secondary Analysis of a Randomized Clinical Trial. JAMA Cardiol. 2022 Nov 1;7(11):1138-1146. Open reference URL https://web.pathway.md/studies/recm7uMmwl1NrbkZk 2/2

6/29/23, 11:45 PM SPRINT Pathway Feedback Search Clinical Topics Home Studies SPRINT SPRINT Disease Hypertension Trial question What is the role of intensive BP control in nondiabetic hypertensive patients who are at an increased cardiovascular risk? Study design Multi-center Open label RCT Population Characteristics of study participants 36.0% female N = 9361 64.0% male 9361 patients (3332 female, 6029 male) Inclusion criteria: patients with a systolic BP 130 mmHg and an increased cardiovascular risk, but without diabetes Key exclusion criteria: diabetes mellitus, prior stroke, or CKD Interventions N=4678 intensive BP reduction (systolic blood-pressure target of < 120 mmHg) N=4683 standard BP management (systolic blood-pressure target of < 140 mmHg) Primary outcome https://web.pathway.md/studies/recAHD1gOju2thSrB 1/2 6/29/23, 11:45 PM SPRINT Pathway Myocardial infarction, other acute coronary syndromes, stroke, heart failure, or death from cardiovascular causes 6.8 % 6.8 5.2 5.1 % 3.4 % Significant decrease 1.7 % NNT = 63 0.0 % Intensive blood pressure reduction Standard blood pressure management Significant decrease in myocardial infarction, other acute coronary syndromes, stroke, HF, or death from cardiovascular causes (5.2% vs. 6.8%; HR 0.75, 95% CI 0.64 to 0.89) Secondary outcomes Significant decrease in death from any cause (3.3% vs. 4.5%; HR 0.73, 95% CI 0.6 to 0.9) Safety outcomes No significant differences in serious adverse events (38.3% vs. 37.1%, p=0.25). Significant differences in serious adverse events as possibly or definitely related to the intervention (4.7% vs. 2.5%, p < 0.001), hypotension (2.4% vs. 1.4%, p = 0.001), and AKI or acute renal failure (4.1% vs. 2.5%, p < 0.001). Conclusion In patients with a systolic BP 130 mmHg and an increased cardiovascular risk, but without diabetes, intensive BP reduction was superior to standard BP management with respect to myocardial infarction, other acute coronary syndromes, stroke, HF, or death from cardiovascular causes. Reference SPRINT Research Group, Wright JT Jr, Williamson JD et al. A Randomized Trial of Intensive versus Standard Blood-Pressure Control. N Engl J Med. 2015 Nov 26;373(22):2103-16. Open reference URL https://web.pathway.md/studies/recAHD1gOju2thSrB 2/2

6/29/23, 11:45 PM SPRINT-MIND Pathway Feedback Search Clinical Topics Home Studies SPRINT MIND SPRINT MIND Disease Disease Dementia Hypertension Trial question What is the effect of intensive BP control to reduce the risk of probable dementia in ambulatory adults with hypertension who were at an increased risk of CVD? Study design Multi-center Open label RCT Population Characteristics of study participants 36.0% female N = 9361 64.0% male 9361 patients (3332 female, 6029 male) Inclusion criteria: ambulatory adult patients ( 50 years of age) with hypertension but without diabetes or history of stroke who had an increased cardiovascular risk Key exclusion criteria: nursing home residents, diagnosis of dementia, use of dementia therapy medications, diabetes mellitus, history of stroke Interventions N=4678 intensive BP reduction (systolic BP goal of < 120 mmHg with antihypertensives) N=4683 standard BP management (systemic BP goal of < 140 mmHg with antihypertensive medications) https://web.pathway.md/studies/recDAGML8mqX75pXd 1/2 6/29/23, 11:45 PM SPRINT-MIND Pathway Primary outcome Incidence of adjudicated probable dementia at a median follow-up of 5.11 years 8.6/1000 py 8.6 7.2 6.4/1000 py 4.3/1000 py 2.1/1000 py No significant difference 0.0/1000 py Intensive blood pressure reduction Standard blood pressure management No significant difference in the incidence of adjudicated probable dementia at a median follow-up of 5.11 years (7.2 /1000 py vs. 8.6 /1000 py; HR 0.83, 95% CI 0.67 to 1.04) Secondary outcomes Significant decrease in the incidence of mild cognitive impairment (14.6 /1000 py vs. 18.3 /1000 py; HR 0.81, 95% CI 0.69 to 0.95) Significant decrease in mild cognitive impairment or probable dementia (20.2 vs. 24.1; HR 0.85, 95% CI 0.74 to 0.97) Safety outcomes No significant difference in interaction between treatment group and prespecified subgroups with respect to the composite of MCI and probable dementia. Conclusion In ambulatory adult patients ( 50 years of age) with hypertension but without diabetes or history of stroke who had an increased cardiovascular risk, intensive BP reduction was not superior to standard BP management with respect to the incidence of adjudicated probable dementia at a median follow-up of 5.11 years. Reference SPRINT MIND Investigators for the SPRINT Research Group, Williamson JD, Pajewski NM et al. Effect of Intensive vs Standard Blood Pressure Control on Probable Dementia: A Randomized Clinical Trial. JAMA. 2019 Feb 12;321(6):553-561. Open reference URL https://web.pathway.md/studies/recDAGML8mqX75pXd 2/2

6/29/23, 11:45 PM SPS3 Clopidogrel-ASA Pathway Feedback Search Clinical Topics Home Studies SPS3 Clopidogrel-ASA SPS3 Clopidogrel-ASA Disease Acute ischemic stroke Trial question What is the effect of combination of clopidogrel to aspirin in patients with recent lacunar stroke? Study design Multi-center Double blinded RCT Population Characteristics of study participants 37.0% female N = 3020 63.0% male 3020 patients (1118 female, 1902 male) Inclusion criteria: patients with recent symptomatic lacunar infarcts identified by MRI Key exclusion criteria: MRI evidence of a recent or remote cortical infarct, a large subcortical infarct > 1.5 cm in diameter), intracerebral hemorrhage, disabling stroke, previous intracranial hemorrhage, or cortical ischemic stroke Interventions N=1517 clopidogrel (75 mg clopidogrel plus 325 mg aspirin daily) N=1503 placebo (placebo plus 325 mg aspirin daily) Primary outcome Incidence of recurrent stroke, at a mean follow-up of 3.4 years https://web.pathway.md/studies/recv7w8ocA4GfTvKG 1/2 6/29/23, 11:45 PM SPS3 Clopidogrel-ASA Pathway 2.7 % / y 2.7 2.5 2.0 % / y 1.4 % / y 0.7 % / y No significant difference 0.0 % / y Clopidogrel Placebo No significant difference in the incidence of recurrent stroke, at a mean follow-up of 3.4 years (2.5% / y vs. 2.7% / y; HR 0.92, 95% CI 0.72 to 1.16) Secondary outcomes Significant increase in the incidence of death from any cause (2.1% / y vs. 1.4% / y; HR 1.52, 95% CI 1.14 to 2.04) No significant difference in the incidence of recurrent ischemic stroke (2% / y vs. 2.4% / y; HR 0.82, 95% CI 0.63 to 1.09) No significant difference in the incidence of disabling or fatal stroke (0.84% / y vs. 0.78% / y; HR 1.06, 95% CI 0.69 to 1.64) Safety outcomes Significant differences in major hemorrhage (2.1% vs. 1.1% per year, p < 0.001; HR 1.97, 95% CI 1.41-2.71). Conclusion In patients with recent symptomatic lacunar infarcts identified by MRI, clopidogrel was not superior to placebo with respect to the incidence of recurrent stroke, at a mean follow-up of 3.4 years. Reference SPS Investigators, Benavente OR, Hart RG et al. Effects of clopidogrel added to aspirin in patients with recent lacunar stroke. N Engl J Med. 2012 Aug 30;367(9):817-25. Open reference URL https://web.pathway.md/studies/recv7w8ocA4GfTvKG 2/2

6/29/23, 11:45 PM SPS3-BP Pathway Feedback Search Clinical Topics Home Studies SPS3 BP SPS3 BP Disease Acute ischemic stroke Trial question What is the effect of targeting lower systolic BPs in patients with recent lacunar stroke? Study design Multi-center Open label RCT Population Characteristics of study participants 37.0% female N = 3020 63.0% male 3020 patients (1117 female, 1903 male) Inclusion criteria: patients with recent lacunar stroke Key exclusion criteria: disabling stroke, previous intracranial hemorrhage (excluding traumatic), or cortical ischemic stroke Interventions N=1501 lower BP target (systolic BP target < 130 mmHg) N=1519 higher BP target (systolic BP target of 130-149 mmHg) Primary outcome Ischemic or hemorrhagic stroke 2.8 % 2.77 https://web.pathway.md/studies/recI8N4lPXRnJlAkq 1/2 6/29/23, 11:45 PM SPS3-BP Pathway 2.25 2.1 % 1.4 % 0.7 % No significant difference 0.0 % Lower blood pressure target Higher blood pressure target No significant difference in ischemic or hemorrhagic stroke (2.25% vs. 2.77%; HR 0.81, 95% CI 0.64 to 1.03) Secondary outcomes Significant decrease in intracerebral hemorrhage (0.11% vs. 0.29%; HR 0.37, 95% CI 0.15 to 0.95) No significant difference in disabling or fatal stroke (0.72% vs. 0.89%; HR 0.81, 95% CI 0.53 to 1.23) No significant difference in myocardial infarction (0.62% vs. 0.7%; HR 0.88, 95% CI 0.68 to 1.04) Safety outcomes No significant differences in serious complications of hypotension, including syncope. Conclusion In patients with recent lacunar stroke, lower BP target was not superior to higher BP target with respect to ischemic or hemorrhagic stroke. Reference SPS Study Group, Benavente OR, Coffey CS et al. Blood-pressure targets in patients with recent lacunar stroke: the SPS3 randomised trial. Lancet. 2013 Aug 10;382(9891):507-15. Open reference URL https://web.pathway.md/studies/recI8N4lPXRnJlAkq 2/2

6/29/23, 11:45 PM SPYRAL HTN-ON MED Pathway Feedback Search Clinical Topics Home Studies SPYRAL HTN ON MED SPYRAL HTN ON MED Disease Hypertension Trial question What is the effect of renal denervation on BP in patients with uncontrolled hypertension on antihypertensive medications? Study design Multi-center Single blinded RCT Population Characteristics of study participants 16.0% female N = 80 84.0% male 80 patients (13 female, 67 male) Inclusion criteria: patients with uncontrolled hypertension with office systolic BP between 150-180 mmHg and and diastolic BP 90 mmHg and ambulatory systolic BP between 140-170 mmHg who were on 1-3 antihypertensive drugs with stable doses for at least 6 weeks Key exclusion criteria: lack of appropriate renal artery anatomy, eGFR < 45, T1DM mellitus, poorly-controlled T2DM mellitus, primary pulmonary hypertension Interventions N=38 renal denervation (renal angiography and renal denervation with Symplicity Spyral multi- electrode renal denervation system) N=42 sham intervention (renal angiogram with sensory masking post-angiogram) https://web.pathway.md/studies/reckxHgW0xqat4kFu 1/2 6/29/23, 11:45 PM SPYRAL HTN-ON MED Pathway Primary outcome Significant decrease in change in 24-hour ambulatory systolic BP and diastolic BP from baseline to 6 months (-9 mmHg vs. -1.6 mmHg; AD -7 mmHg, 95% CI -12 to -2.1) Secondary outcomes Significant decrease in change in office systolic BP and diastolic BP from baseline to 6 months (-9.4 mmHg vs. -2.6 mmHg; AD -6.6 mmHg, 95% CI -12.4 to -0.9) No significant difference in change in 24-hour HR at 6 months (-3.7 bpm vs. -1.5 bpm; AD -2.3 bpm, 95% CI -5.1 to 0.4) No significant difference in change in office HR at 6 months (-5.1 bpm vs. -3.2 bpm; AD -1.4 bpm, 95% CI -4.7 to 1.8) Safety outcomes No significant differences in medication adherence, adverse events. Significant difference in mean changes in ambulatory 24-hour systolic BP (-4.3 mmHg vs. -0.7 mmHg) and diastolic BP (-4.2 mmHg vs. -0.8 mmHg). Conclusion In patients with uncontrolled hypertension with office systolic BP between 150-180 mmHg and and diastolic BP 90 mmHg and ambulatory systolic BP between 140-170 mmHg who were on 1-3 antihypertensive drugs with stable doses for at least 6 weeks, renal denervation was superior to sham intervention with respect to change in 24-hour ambulatory systolic BP and diastolic BP from baseline to 6 months. Reference Kandzari DE, Bohm M, Mahfoud F et al. Effect of renal denervation on blood pressure in the presence of antihypertensive drugs: 6-month efficacy and safety results from the SPYRAL HTN-ON MED proof-of-concept randomised trial. Lancet. 2018 Jun 9;391(10137):2346-2355. Open reference URL https://web.pathway.md/studies/reckxHgW0xqat4kFu 2/2

6/29/23, 11:45 PM SSaSS Pathway Feedback Search Clinical Topics Home Studies SSaSS SSaSS Disease Disease Acute ischemic stroke Hypertension Trial question Is salt substitution superior to regular salt in patients with a history of stroke? Study design Multi-center Open label RCT Population Characteristics of study participants 50.0% female N = 20995 50.0% male 20995 patients (10393 female, 10602 male) Inclusion criteria: adult participants 60 years of age with a history of stroke and hypertension Key exclusion criteria: participant or family member with a potential contraindication to salt substitute, unlikely to live > 6 months, eats most meals outside home Interventions N=10504 salt substitute (75% sodium chloride and 25% potassium chloride by mass) N=10491 regular salt (100% sodium chloride) Primary outcome Incidence of stroke 33.6/1K py 33.65 https://web.pathway.md/studies/recluf3dW4Al66wZ3 1/2 6/29/23, 11:45 PM py SSaSS Pathway 33 65 29.14 25.2/1K py 16.8/1K py 8.4/1K py Significant decrease 0.0/1K py Salt substitute Regular salt Significant decrease in the incidence of stroke (29.14 events /1000 py vs. 33.65 events /1000 py; RR 0.86, 95% CI 0.77 to 0.96) Secondary outcomes Significant decrease in the incidence of major adverse cardiovascular events (49.09 events /1000 py vs. 56.29 events /1000 py; RR 0.87, 95% CI 0.8 to 0.94) Borderline significant decrease in the incidence of death from vascular causes (22.9 events /1000 py vs. 26.3 events /1000 py; RR 0.87, 95% CI 0.79 to 0.96) Safety outcomes No significant difference in clinical hyperkalemia. Conclusion In adult participants 60 years of age with a history of stroke and hypertension, salt substitute was superior to regular salt with respect to the incidence of stroke. Reference Bruce Neal, Yangfeng Wu, Xiangxian Feng et al. Effect of Salt Substitution on Cardiovascular Events and Death. N Engl J Med. 2021 Sep 16;385(12):1067-1077. Open reference URL https://web.pathway.md/studies/recluf3dW4Al66wZ3 2/2

6/29/23, 11:45 PM STAMPEDE Pathway Feedback Search Clinical Topics Home Studies STAMPEDE STAMPEDE Disease Disease Diabetes mellitus type 2 Obesity Reference Schauer PR, Kashyap SR, Wolski K et al. Bariatric surgery versus intensive medical therapy in obese patients with diabetes. N Engl J Med. 2012 Apr 26;366(17):1567-76. Open reference URL https://web.pathway.md/studies/recDwcxRgcEh3Msxx 1/1

6/29/23, 11:45 PM STAR Pathway Feedback Search Clinical Topics Home Studies STAR STAR Trial question What is the effect of raloxifene in postmenopausal women with an increased risk of invasive breast cancer? Study design Multi-center Double blinded RCT Population 19747 female patients Inclusion criteria: postmenopausal women with a mean age of 58.5 years who have an increased 5-year breast cancer risk Key exclusion criteria: age < 35 years or premenopausal; receipt of tamoxifen, raloxifene, hormone therapy, oral contraceptives, or androgens for at least the previous 3 months; history of stroke, PE, or deep vein thrombosis uncontrolled AF, uncontrolled diabetes, or uncontrolled hypertension Interventions N=9745 raloxifene (60 mg/day for a maximum of 5 years) N=9726 tamoxifen (20 mg/day PO for a maximum of 5 years) Primary outcome Invasive breast cancer 0.4 % 0.44 0.43 0.3 % 0.2 % 0.1 % No significant difference 0.0 % Raloxifene Tamoxifen No significant difference in invasive breast cancer (0.44% vs. 0.43%; RR 1.02, 95% CI 0.82 to 1.28) Secondary outcomes https://web.pathway.md/studies/rec6TOwKD2ksvHU85 1/2 6/29/23, 11:45 PM STAR Pathway No significant difference in noninvasive breast cancer (0.21% vs. 0.15%; RR 1.4, 95% CI 0.98 to 2) No significant difference in uterine cancer (0.13% vs. 0.2%; RR 0.62, 95% CI 0.35 to 1.08) Borderline significant decrease in thromboembolic events (0.26% vs. 0.37%; RR 0.7, 95% CI 0.54 to 0.91) Safety outcomes No significant differences in deaths, osteoporotic fractures, stroke, ischemic heart disease. Significant differences in cataracts (0.97% vs. 1.23%), cataract surgeries (0.66% vs. 0.80%). Conclusion In postmenopausal women with a mean age of 58.5 years who have an increased 5-year breast cancer risk, raloxifene was not superior to tamoxifen with respect to invasive breast cancer. Reference Vogel VG, Costantino JP, Wickerham DL et al. Effects of tamoxifen vs raloxifene on the risk of developing invasive breast cancer and other disease outcomes: the NSABP Study of Tamoxifen and Raloxifene (STAR) P-2 trial. JAMA. 2006 Jun 21;295(23):2727-41. Open reference URL https://web.pathway.md/studies/rec6TOwKD2ksvHU85 2/2

6/29/23, 11:45 PM STARRT-AKI (secondary analysis, accelerated RRT) Pathway Feedback Search Clinical Topics Home Studies STARRT AKI (secondary analysis, accelerated RRT STARRT AKI (secondary analysis, accelerated RRT Disease Disease Acute kidney injury Chronic kidney disease Trial question What is the effect of accelerated RRT initiation in patients with pre-hospital measures of kidney function? Study design Multi-center Open label RCT Population Characteristics of study participants 31.0% female N = 1121 69.0% male 1121 patients (353 female, 768 male) Inclusion criteria: patients with documented pre-existing eGFR data prior to hospitalization Key exclusion criteria: eGFR < 20 mL/min/1.73 m Interventions N=561 accelerated strategy (initiation of RRT within 12 hours) N=560 standard strategy (RRT initiation discouraged until development of conventional indications or persistent AKI for 72 hours) Primary outcome Death in patients with chronic kidney disease at day 90 https://web.pathway.md/studies/recAzAUhW9ZwdFnVO 1/2 6/29/23, 11:45 PM STARRT-AKI (secondary analysis, accelerated RRT) Pathway 47.4 % 47.4 47 35.5 % 23.7 % 11.8 % No significant difference 0.0 % Accelerated strategy Standard strategy No significant difference in death in patients with CKD at day 90 (47% vs. 47.4%; OR 0.98, 95% CI 0.67 to 1.44) Secondary outcomes No significant difference in death in patients without CKD at day 90 (40.9% vs. 38%; OR 1.13, 95% CI 0.83 to 1.53) Borderline significant increase in RRT dependence in patients with CKD at day 90 (19.8% vs. 7.2%; OR 3.18, 95% CI 1.41 to 7.91) No significant difference in RRT dependence in patients without CKD at day 90 (6.5% vs. 8.9%; OR 0.71, 95% CI 0.34 to 1.47) Conclusion In patients with documented pre-existing eGFR data prior to hospitalization, accelerated strategy was not superior to standard strategy with respect to death in patients with CKD at day 90. Reference Sean M Bagshaw, Ary Serpa Neto, Orla Smith et al. Impact of renal-replacement therapy strategies on outcomes for patients with chronic kidney disease: a secondary analysis of the STARRT-AKI trial. Intensive Care Med. 2022 Dec;48(12):1736-1750. Open reference URL https://web.pathway.md/studies/recAzAUhW9ZwdFnVO 2/2

6/29/23, 11:45 PM STARRT-AKI (secondary analysis, CKD) Pathway Feedback Search Clinical Topics Home Studies STARRT AKI (secondary analysis, CKD STARRT AKI (secondary analysis, CKD Disease Disease Acute kidney injury Chronic kidney disease Trial question What is the effect of RRT initiation strategy in patients with and without CKD? Study design Multi-center Open label RCT Population Characteristics of study participants 31.0% female N = 1121 69.0% male 1121 patients (353 female, 768 male) Inclusion criteria: patients with documented pre-existing eGFR data prior to hospitalization Key exclusion criteria: eGFR < 20 mL/min/1.73 m Interventions N=689 renal-replacement therapy for patients with CKD (eGFR 59 mL/min/1.73 m ) N=432 renal-replacement therapy for patients without CKD (eGFR > 59 mL/min/1.73 m ) Primary outcome Death from all causes at day 90 47.2 47.2 % 39.5 https://web.pathway.md/studies/rec04XqwVz6tMXTTR 1/2 6/29/23, 11:45 PM STARRT-AKI (secondary analysis, CKD) Pathway 39.5 35.4 % 23.6 % 11.8 % No significant difference 0.0 % Renal-replacement therapy for patients with chronic kidney disease Renal-replacement therapy for patients without chronic kidney disease No significant difference in death from all causes at day 90 (47.2% vs. 39.5%; aOR 1.05, 95% CI 0.79 to 1.41) Secondary outcomes Significant increase in RRT dependence at day 90 (13.7% vs. 7.7%; aOR 1.89, 95% CI 1.05 to 3.43) No significant difference in RRT-free days at day 90 (39.7 days vs. 47.9 days; MD -3.24, 95% CI -8.3 to 1.82) No significant difference in death in the hospital (40.6% vs. 35.6%; OR 1.03, 95% CI 0.76 to 1.37) Safety outcomes No significant difference in adverse events. Conclusion In patients with documented pre-existing eGFR data prior to hospitalization, renal-replacement therapy for patients with CKD was not superior to renal-replacement therapy for patients without CKD with respect to death from all causes at day 90. Reference Sean M Bagshaw, Ary Serpa Neto, Orla Smith et al. Impact of renal-replacement therapy strategies on outcomes for patients with chronic kidney disease: a secondary analysis of the STARRT-AKI trial. Intensive Care Med. 2022 Dec;48(12):1736-1750. Open reference URL https://web.pathway.md/studies/rec04XqwVz6tMXTTR 2/2

6/29/23, 11:45 PM STARRT-AKI Pathway Feedback Search Clinical Topics Home Studies STARRT AKI STARRT AKI Disease Acute kidney injury Trial question What is the role of accelerated initiation of RRT in critically ill patients with AKI? Study design Multi-center Open label RCT Population Characteristics of study participants 32.0% female N = 3019 68.0% male 3019 patients (937 female, 1990 male) Inclusion criteria: critically ill patients with severe AKI Key exclusion criteria: potassium > 5.5 mmol/L; bicarbonate < 15 mmol/L; any RRT in preceding 2 months; kidney transplant within the past year; advanced CKD; kidney obstruction, glomerulonephritis, vasculitis, microangiopathy, or acute interstitial nephritis Interventions N=1512 an accelerated strategy (initiation of RRT within 12 hours of meeting full eligibility criteria) N=1507 a standard strategy (initiation of RRT discouraged until development of conventional indications or persistent AKI for 72 hours) Primary outcome https://web.pathway.md/studies/rec1mY5ym53IFoluo 1/2 6/29/23, 11:45 PM STARRT-AKI Pathway Death from any cause at 90 days 43.9 % 43.9 43.7 32.9 % 21.9 % 11.0 % No significant difference 0.0 % An accelerated strategy A standard strategy No significant difference in death from any cause at 90 days (43.9% vs. 43.7%; RR 1, 95% CI 0.93 to 1.09) Secondary outcomes Borderline significant increase in renal replacement dependence among survivors at 90 days (10.4% vs. 6%; RR 1.74, 95% CI 1.24 to 2.43) No significant difference in death or renal replacement dependence at 90 days (50% vs. 47.3%; RR 1.06, 95% CI 0.98 to 1.14) No significant difference in major adverse kidney events (76.7% vs. 77.1%; RR 0.99, 99% CI 0.95 to 1.04) Safety outcomes No significant difference in serious adverse events. Significant differences in any adverse event (23.0% vs. 16.5%), hypotension (8.7% vs. 5.6%), hypophosphatemia (7.5% vs. 4.2%). Conclusion In critically ill patients with severe AKI, an accelerated strategy was not superior to a standard strategy with respect to death from any cause at 90 days. Reference STARRT-AKI Investigators, Canadian Critical Care Trials Group, Australian and New Zealand Intensive Care Society Clinical Trials Group et al. Timing of Initiation of Renal-Replacement Therapy in Acute Kidney Injury. N Engl J Med. 2020 Jul 16;383(3):240-251. Open reference URL https://web.pathway.md/studies/rec1mY5ym53IFoluo 2/2

6/29/23, 11:45 PM STARS E3 Pathway Feedback Search Clinical Topics Home Studies STARS E3 STARS E3 Disease Knee osteoarthritis Trial question What is the role of edoxaban for thromboprophylaxis in patients who underwent total knee arthroplasty? Study design Multi-center Double blinded RCT Population Characteristics of study participants 79.5% female N = 716 20.5% male 716 patients (474 female, 120 male) Inclusion criteria: patients who underwent total knee arthroplasty Key exclusion criteria: increased risk of bleeding; high risk for thromboembolism; body weight < 40 kg; severe renal impairment (CrCl < 30 mL/min); hepatic dysfunction; or pregnant or lactating women Interventions N=360 edoxaban (30 mg once daily PO beginning 6 to 24 hours postsurgery for 11 to 14 days) N=356 enoxaparin (2,000 IU (equivalent to 20 mg) SC BID beginning 24 to 36 hours postsurgery for 11 to 14 days) https://web.pathway.md/studies/recoRCFyuUcypm7p5 1/2 6/29/23, 11:45 PM STARS E3 Pathway Primary outcome Symptomatic pulmonary embolism and symptomatic and asymptomatic deep venous thrombosis 13.9 % 13.9 10.4 % 7.4 7.0 % Significant decrease 3.5 % NNT = 15 0.0 % Edoxaban Enoxaparin Significant decrease in symptomatic PE and symptomatic and asymptomatic DVT (7.4% vs. 13.9%; RR 0.53, 95% CI 0.9 to 0.96) Safety outcomes No significant differences in serious adverse events, major bleeding events (1.1% vs. 0.3%, p=0.373) and major or CRNM bleeding (6.2% vs. 3.7%, p=0.129). Conclusion In patients who underwent total knee arthroplasty, edoxaban was superior to enoxaparin with respect to symptomatic PE and symptomatic and asymptomatic DVT. Reference Fuji T, Wang CJ, Fujita S et al. Safety and efficacy of edoxaban, an oral factor Xa inhibitor, versus enoxaparin for thromboprophylaxis after total knee arthroplasty: the STARS E-3 trial. Thromb Res. 2014 Dec;134(6):1198-204. Open reference URL https://web.pathway.md/studies/recoRCFyuUcypm7p5 2/2

6/29/23, 11:45 PM STELLAR Pathway Feedback Search Clinical Topics Home Studies STELLAR STELLAR Disease Pulmonary hypertension Trial question What is the role of sotatercept in patients with pulmonary arterial hypertension? Study design Multi-center Double blinded RCT Population Characteristics of study participants 79.0% female N = 323 21.0% male 323 patients (256 female, 67 male) Inclusion criteria: adult patients with pulmonary arterial hypertension who were receiving stable background therapy Key exclusion criteria: pulmonary arterial hypertension subtypes associated with portopulmonary disease; schistosomiasis; human immunodeficiency virus infection, or VOD Interventions N=163 sotatercept (a subcutaneous starting dose of 0.3 mg/kg with a target dose of 0.7 mg/kg every 3 weeks) N=160 placebo (matching placebo every 3 weeks) Primary outcome https://web.pathway.md/studies/rectWIu2sb5h0nA6E 1/2 6/29/23, 11:45 PM STELLAR Pathway Improvement in median 6-minute walk distance at week 24 34.4 m 34.4 25.8 m 17.2 m 8.6 m Significant increase 1 0.0 m Sotatercept Placebo Significant increase in improvement in the median 6-minute walk distance at week 24 (34.4 m vs. 1 m; AD 33.4 m, 95% CI 13.58 to 53.22) Secondary outcomes Significant increase in composite of multicomponent improvement of 6-minute walk distance, N- terminal pro-B-type natriuretic peptide level, and WHO functional class (38.9% vs. 10.1%; AD 28.8%, 95% CI 11.71 to 45.89) Significant increase in median reduction in pulmonary vascular resistance at week 24 (165.1 dyn.sec.cm-5 vs. -32.8 dyn.sec.cm-5; AD 197.9 dyn.sec.cm-5, 95% CI 80.47 to 315.33) Significant increase in median reduction in N-terminal pro-B-type natriuretic peptide level at week 24 (230.3 pg/mL vs. -58.6 pg/mL; AD 288.9 pg/mL, 95% CI 117.48 to 460.32) Safety outcomes No significant difference in adverse events. Conclusion In adult patients with pulmonary arterial hypertension who were receiving stable background therapy, sotatercept was superior to placebo with respect to improvement in the median 6-minute walk distance at week 24. Reference Marius M Hoeper, David B Badesch, H Ardeschir Ghofrani et al. Phase 3 Trial of Sotatercept for Treatment of Pulmonary Arterial Hypertension. N Engl J Med. 2023 Apr 20;388(16):1478-1490. Open reference URL https://web.pathway.md/studies/rectWIu2sb5h0nA6E 2/2

6/29/23, 11:45 PM STEP 1 Pathway Feedback Search Clinical Topics Home Studies STEP 1 STEP 1 Disease Obesity Trial question What is the role of once-weekly semaglutide as an adjunct to lifestyle intervention in adults with overweight or obesity? Study design Multi-center Double blinded RCT Population Characteristics of study participants 66.2% female N = 1961 33.8% male 1961 patients (955 female, 498 male) Inclusion criteria: patients with a body-mass index of 30 (or 27 with 1 weight-related coexisting condition) who did not have diabetes Key exclusion criteria: HbA1c 6.5%, self-reported change in body weight > 5 kg (11 lbs) within 90 days before screening, previous treatment with glucose-lowering agents or any antiobesity medications within the past 90 days before screening Interventions N=1306 semaglutide (2.4 mg once-weekly plus diet and physical activity counseling) N=655 placebo (matching placebo subcutaneous injection once-weekly plus diet and physical activity counseling) https://web.pathway.md/studies/recnfrfXWGE6Mioou 1/2 6/29/23, 11:45 PM STEP 1 Pathway Primary outcome Relative weight reduction at week 68 14.9 % 14.9 11.2 % 7.5 % Significant increase 3.7 % NNT = 8 2.4 0.0 % Semaglutide Placebo Significant increase in relative weight reduction at week 68 (14.9% vs. 2.4%; AD 12.4%, 95% CI 11.5 to 13.4) Secondary outcomes Significant increase in the percentage of patients achieving a weight reduction of 10% at week 68 (69.1% vs. 12%; OR 14.7, 95% CI 11.1 to 19.4) Significant increase in the percentage of patients achieving a reduction in weight by 15% at week 68 (50.5% vs. 4.9%; OR 19.3, 95% CI 12.9 to 28.8) Significant increase in absolute weight reduction from baseline to week 68 (15.3 kg vs. 2.6 kg; AD 12.7 kg, 95% CI 11.7 to 13.7) Safety outcomes No significant difference in overall adverse events. Significant differences in serious adverse events (9.8% vs. 6.4%), gastrointestinal disorders (74.2% vs. 47.9%), treatment discontinuation due to gastrointestinal events (4.5% vs. 0.8%). Conclusion In patients with a body-mass index of 30 (or 27 with 1 weight-related coexisting condition) who did not have diabetes, semaglutide was superior to placebo with respect to relative weight reduction at week 68. Reference John P.H. Wilding, D.M., Rachel L. Batterham et al. Once-Weekly Semaglutide in Adults with Overweight or Obesity. N Engl J Med. 2021 Feb 10. Open reference URL https://web.pathway.md/studies/recnfrfXWGE6Mioou 2/2

6/29/23, 11:45 PM STEP 8 Pathway Feedback Search Clinical Topics Home Studies STEP 8 STEP 8 Disease Obesity Trial question Is weekly subcutaneous semaglutide superior to daily liraglutide in adults with overweight or obesity without diabetes? Study design Multi-center Open label RCT Population Characteristics of study participants 78.0% female N = 338 22.0% male 338 patients (265 female, 73 male) Inclusion criteria: non-diabetic adults with BMI of 30, or BMI 27 plus at least one weight- related comorbidities Key exclusion criteria: HbA1c 48 mmol/mol; history of type 1 or T2DM mellitus; self-reported change in body weight 5 kg at 90 days of screening Interventions N=126 semaglutide (subcutaneous dose of 2.4 mg once weekly) N=127 liraglutide (subcutaneous dose of 3.0 mg once daily) Primary outcome https://web.pathway.md/studies/recsthZZCH8iYBWt1 1/2 6/29/23, 11:45 PM STEP 8 Pathway Body weight reduction 15.8 % 15.8 11.9 % 7.9 % 6.4 Significant increase 4.0 % NNT = 11 0.0 % Semaglutide Liraglutide Significant increase in body weight reduction (15.8% vs. 6.4%; AD 9.4%, 95% CI 6.8 to 12) Secondary outcomes Significant increase in the percentage of patients achieving a weight reduction of 10% (70.9% vs. 25.6%; OR 6.3, 95% CI 3.5 to 11.2) Significant increase in the percentage of patients achieving a weight reduction of 15% (55.6% vs. 12%; OR 7.9, 95% CI 4.1 to 15.4) Significant increase in the percentage of patients achieving a weight reduction of 20% (38.5% vs. 6%; OR 8.2, 95% CI 3.5 to 19.1) Safety outcomes No significant difference in gastrointestinal adverse events. Conclusion In non-diabetic adults with BMI of 30, or BMI 27 plus at least one weight-related comorbidities, semaglutide was superior to liraglutide with respect to body weight reduction. Reference Domenica M Rubino, Frank L Greenway, Usman Khalid et al. Effect of Weekly Subcutaneous Semaglutide vs Daily Liraglutide on Body Weight in Adults With Overweight or Obesity Without Diabetes: The STEP 8 Randomized Clinical Trial. JAMA. 2022 Jan 11;327(2):138-150. Open reference URL https://web.pathway.md/studies/recsthZZCH8iYBWt1 2/2

6/29/23, 11:45 PM STHLM3MR-2 Pathway Feedback Search Clinical Topics Home Studies STHLM3MR 2 STHLM3MR 2 Disease Prostate cancer Trial question Is MRI with targeted biopsy noninferior to standard biopsy in prostate cancer screening? Study design Multi-center Open label RCT Population 1532 male patients Inclusion criteria: men aged 50 to 74 years with PSA levels 3 ng/mL Key exclusion criteria: previous diagnosis of prostate cancer; a prostate biopsy within 60 days of invitation; contraindication to MRI; severe illness Interventions N=929 MRI-targeted biopsy (MRI with targeted and standard biopsy if the MRI results suggested prostate cancer) N=603 standard biopsy (systematic biopsy of the prostate if PSA 3 ng/mL) Primary outcome Detection of a clinically significant cancer 21.0 % 21 18 15.8 % 10.5 % Difference not exceeding nonferiority margin 5.3 % 0.0 % https://web.pathway.md/studies/recVpm2i7SCqs2DnF 1/2 6/29/23, 11:45 PM STHLM3MR-2 Pathway MRI-targeted biopsy Standard biopsy Difference not exceeding nonferiority margin in the detection of a clinically significant cancer (21% vs. 18%; AD 3%, 95% CI -1 to 7) Secondary outcomes Significant decrease in the detection of a clinically insignificant cancer (4% vs. 12%; ARD -8, 95% CI -11 to -5) Significant decrease in benign biopsy findings (11% vs. 43%; ARD -32, 95% CI -36 to -27) Safety outcomes No significant difference in post-biopsy infections and hospitalization. Conclusion In men aged 50 to 74 years with PSA levels 3 ng/mL, MRI-targeted biopsy was noninferior to standard biopsy with respect to the detection of a clinically significant cancer. Reference Martin Eklund, Fredrik J derling, Andrea Discacciati et al. MRI-Targeted or Standard Biopsy in Prostate Cancer Screening. N Engl J Med. 2021 Sep 2;385(10):908-920. Open reference URL https://web.pathway.md/studies/recVpm2i7SCqs2DnF 2/2

6/29/23, 11:56 PM STICH Pathway Feedback Search Clinical Topics Home Studies STICH STICH Disease Disease Coronary artery disease Heart failure Trial question What is the role of coronary artery bypass surgery in patients with LV dysfunction? Study design Multi-center Open label RCT Population Characteristics of study participants 12.0% female N = 1212 88.0% male 1212 patients (148 female, 1064 male) Inclusion criteria: patients with LV dysfunction (LVEF 35%) and coronary artery disease amenable to CABG Key exclusion criteria: plan for percutaneous intervention for CAD, cardiogenic shock within 72 hours of randomization, recent acute MI as a cause of LV dysfunction, noncardiac illness with a life expectancy of < 3 years, or history of > 1 coronary bypass operation Interventions N=610 CABG (CABG plus medical therapy) N=602 medical therapy (medical therapy alone) Primary outcome https://web.pathway.md/studies/rec2FU0WhnSIB4re7 1/2 6/29/23, 11:56 PM STICH Pathway All-cause death 41.0 % 41 36 30.8 % 20.5 % 10.3 % No significant difference 0.0 % Coronary artery bypass graft Medical therapy No significant difference in all-cause death (36% vs. 41%; HR 0.86, 95% CI 0.72 to 1.04) Secondary outcomes Borderline significant decrease in adjudicated death due to cardiovascular cause (28% vs. 33%; HR 0.81, 95% CI 0.66 to 1) Significant decrease in death from any cause or hospitalization for cardiovascular causes (58% vs. 68%; HR 0.74, 95% CI 0.64 to 0.85) Conclusion In patients with LV dysfunction (LVEF 35%) and coronary artery disease amenable to CABG, CABG was not superior to medical therapy with respect to a all-cause death. Reference Velazquez EJ, Lee KL, Deja MA et al. Coronary-artery bypass surgery in patients with left ventricular dysfunction. N Engl J Med. 2011 Apr 28;364(17):1607-16. Open reference URL https://web.pathway.md/studies/rec2FU0WhnSIB4re7 2/2

6/29/23, 11:57 PM StiL Pathway Feedback Search Clinical Topics Home Studies StiL StiL Disease Mantle cell lymphoma Trial question Is bendamustine plus rituximab noninferior to CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone) plus rituximab as first-line treatment for patients with indolent and mantle cell lymphomas? Study design Multi-center Open label RCT Population 549 patients Inclusion criteria: patients with advanced indolent and mantle cell lymphomas Key exclusion criteria: severe cardiac disease or previous malignancy; in adequate hepatic, renal, or cardiac function; or infection with human immunodeficiency virus or hepatitis B Interventions N=274 bendamustine plus rituximab (intravenous bendamustine 90 mg/m on days 1 and 2 of a 4- week cycle for a maximum of six cycles plus rituximab 375 mg/m on day 1 of each cycle) N=275 R-CHOP (cycles every 3 weeks of cyclophosphamide 750 mg/m , doxorubicin 50 mg/m , and vincristine 1.4 mg/m on day 1, and prednisone 100 mg/day for 5 days for a maximum of six cycles plus rituximab 375 mg/m on day 1 of each cycle) Primary outcome Median progression-free survival 69.5 months 69.5 52.1 months https://web.pathway.md/studies/rec1lPD5QONFM3uOu 1/2 6/29/23, 11:57 PM StiL Pathway 34.8 months 31.2 17.4 months Significant increase 0.0 months Bendamustine plus rituximab R-CHOP Significant increase in median progression-free survival (69.5 months vs. 31.2 months; HR 1.72, 95% CI 1.35 to 2.27) Secondary outcomes Significant increase in complete response (40% vs. 30%; RR 1.33, 95% CI 0.2 to 2.46) Safety outcomes Significant differences in alopecia (0 vs. 100%), hematological toxicity (30% vs. 68%), infections (37% vs. 50%), peripheral neuropathy (7% vs. 29%), stomatitis (6% vs. 19%), and erythematous skin reactions (16% vs. 9%). Conclusion In patients with advanced indolent and mantle cell lymphomas, bendamustine plus rituximab was superior to R-CHOP with respect to median progression-free survival. Reference Rummel MJ, Niederle N, Maschmeyer G et al. Bendamustine plus rituximab versus CHOP plus rituximab as first-line treatment for patients with indolent and mantle-cell lymphomas: an open-label, multicentre, randomised, phase 3 non-inferiority trial. Lancet. 2013 Apr 6;381(9873):1203-10. Open reference URL https://web.pathway.md/studies/rec1lPD5QONFM3uOu 2/2

6/29/23, 11:57 PM Stockl Pathway Feedback Search Clinical Topics Home Studies Stockl Stockl Disease Disease Cardiac arrest Neuromuscular blockade Trial question What is the role of continuous neuromuscular blockade in patients during targeted temperature management after resuscitation from cardiac arrest? Study design Single center Double blinded RCT Population Characteristics of study participants 17.0% female N = 63 83.0% male 63 patients (11 female, 52 male) Inclusion criteria: adult patients who were resuscitated from non-traumatic out-of-hospital cardiac arrest within six hours prior to arrival at the emergency department Key exclusion criteria: known terminal illness, obvious intoxication, pregnancy, a known allergic reaction against rocuronium, history of myasthenia gravis, or known epileptic disease Interventions N=32 continuous neuromuscular blockade (continuous administration of rocuronium 0.25 mg/kg/hour) N=31 bolus neuromuscular blockade (continuous administration of saline supplemented by rocuronium bolus of 0.25 mg/kg administration if demanded) https://web.pathway.md/studies/recdbHjZAqR4zYdPj 1/2 6/29/23, 11:57 PM Stockl Pathway Primary outcome Shivering episodes 94.0 % 94 70.5 % 47.0 % Significant decrease 25 23.5 % NNT = 1 0.0 % Continuous neuromuscular blockade Bolus neuromuscular blockade Significant decrease in shivering episodes (25% vs. 94%; RR 0.27, 95% CI 0.06 to 0.48) Secondary outcomes No significant difference in the rate of overall death after 12 months (47% vs. 39%; HR 1.34, 95% CI 0.63 to 2.87) No significant difference in the rate of favorable neurological outcome after 12 months (53% vs. 55%; RR 0.97, 95% CI 0.61 to 1.53) Significant decrease in length of stay in the ICU (6 days vs. 10 days; AD -4 days, 95% CI -7.62 to -0.38) Safety outcomes No significant differences in signs of polyneuropathy, cooling rate, time to achieve target temperature. Significant differences in doses of midazolam (4.3 mg/kg vs. 5.1 mg/kg), doses of fentanyl (0.062 mg/kg vs. 0.071 mg/kg), cumulative doses of rocuronium (7.8 mg/kg vs. 2.3 mg/kg), earlier awakening (2 days vs. 4 days). Conclusion In adult patients who were resuscitated from non-traumatic out-of-hospital cardiac arrest within six hours prior to arrival at the emergency department, continuous neuromuscular blockade was superior to bolus neuromuscular blockade with respect to shivering episodes. Reference Mathias St ckl, Christoph Testori, Fritz Sterz et al. Continuous versus intermittent neuromuscular blockade in patients during targeted temperature management after resuscitation from cardiac arrest-A randomized, double blinded, double dummy, clinical trial. Resuscitation. 2017 Nov;120:14- 19. Open reference URL https://web.pathway.md/studies/recdbHjZAqR4zYdPj 2/2

6/29/23, 11:56 PM STONE Pathway Feedback Search Clinical Topics Home Studies STONE STONE Disease Nephrolithiasis Trial question What is the effect of tamsulosin on passage of symptomatic ureteral stones < 9 mm in diameter? Study design Multi-center Double blinded RCT Population Characteristics of study participants 27.0% female N = 512 73.0% male 512 patients (139 female, 373 male) Inclusion criteria: adult patients with a symptomatic urinary stone in the ureter < 9 mm in diameter, as demonstrated on CT Key exclusion criteria: taking exclusionary medications, prior kidney/ureter surgery, admitted to hospital, stone 9 mm, bladder stone, concurrent UTI Interventions N=267 tamsulosin (0.4 mg tablet daily for 28 days) N=245 placebo (identical capsule daily for 28 days) Primary outcome Rate of urinary stone passage at the end of 28-day treatment period https://web.pathway.md/studies/recQfraKZdjDDi8IK 1/2 6/29/23, 11:56 PM STONE Pathway 49.6 % 49.6 47.3 37.2 % 24.8 % 12.4 % No significant difference 0.0 % Tamsulosin Placebo No significant difference in the rate of urinary stone passage at the end of 28-day treatment period (49.6% vs. 47.3%; RR 1.05, 95% CI 0.87 to 1.27) Secondary outcomes No significant difference in stone passage on follow-up CT (83.6% vs. 77.6%; RR 1.08, 95% CI 0.95 to 1.22) Safety outcomes No significant difference in adverse events. Conclusion In adult patients with a symptomatic urinary stone in the ureter < 9 mm in diameter, as demonstrated on CT, tamsulosin was not superior to placebo with respect to the rate of urinary stone passage at the end of 28-day treatment period. Reference Meltzer AC, Burrows PK, Wolfson AB et al. Effect of Tamsulosin on Passage of Symptomatic Ureteral Stones: A Randomized Clinical Trial. JAMA Intern Med. 2018 Aug 1;178(8):1051-1057. Open reference URL https://web.pathway.md/studies/recQfraKZdjDDi8IK 2/2

6/29/23, 11:56 PM STOP COVID Pathway Feedback Search Clinical Topics Home Studies STOP COVID STOP COVID Disease COVID 19 infection Trial question Does fluvoxamine prevent clinical deterioration and decrease the severity of the disease in patients with mild COVID-19? Study design Multi-center Double blinded RCT Population Characteristics of study participants 72.0% female N = 152 28.0% male 152 patients (109 female, 43 male) Inclusion criteria: community-living, nonhospitalized adults with confirmed COVID-19 disease, symptom onset within 7 days, and oxygen saturation 92% Key exclusion criteria: illness severe enough to require hospitalization, unstable medical comorbidities (including severe underlying lung disease, decompensated cirrhosis, and congestive HF), immunocompromised state Interventions N=80 fluvoxamine (100 mg TID for 15 days) N=72 placebo (matching placebo capsules TID for 15 days) https://web.pathway.md/studies/recLj7gJUCzBisN2M 1/2 6/29/23, 11:56 PM STOP COVID Pathway Primary outcome Significant decrease in the rate of clinical deterioration within 15 days (ARD -8.3, 95% CI 1.8 to 16.4) Secondary outcomes Significant increase in remaining symptom-free (100% vs. 91.7%; AD 8.3%, 95% CI 0.6 to 18.4) Significant decrease in clinical status on a 7-point scale (AD -0.22, 95% CI -0.41 to -0.04) No significant difference in difference between baseline and final clinical status on a 7-point scale (-5.6 vs. -5.8; AD 0.3, 95% CI -0.8 to 1.4) Safety outcomes No significant difference in other adverse events. Significant differences in serious adverse events (1.3% vs. 6.9%), pneumonia (3.8% vs. 8.3%), gastrointestinal symptoms (1.3% vs. 6.9%). Conclusion In community-living, nonhospitalized adults with confirmed COVID-19 disease, symptom onset within 7 days, and oxygen saturation 92%, fluvoxamine was superior to placebo with respect to the rate of clinical deterioration within 15 days. Reference Eric J Lenze, Caline Mattar, Charles F Zorumski et al. Fluvoxamine vs Placebo and Clinical Deterioration in Outpatients With Symptomatic COVID-19: A Randomized Clinical Trial. JAMA. 2020 Dec 8;324(22):2292-2300. Open reference URL https://web.pathway.md/studies/recLj7gJUCzBisN2M 2/2

6/29/23, 11:57 PM STOP GOUT Pathway Feedback Search Clinical Topics Home Studies STOP GOUT STOP GOUT Disease Gout Trial question Is allopurinol noninferior to febuxostat in patients with gout? Study design Multi-center Double blinded RCT Population Characteristics of study participants 2.0% female N = 940 98.0% male 940 patients (15 female, 925 male) Inclusion criteria: patients with gout and hyperuricemia Key exclusion criteria: stage 4 or 5 CKD; women aged < 50 years; previous solid organ transplantation; previous hematopoietic transplantation; intolerance to study drugs Interventions N=468 allopurinol (oral dose of 100-800 mg daily) N=472 febuxostat (oral dose of 40-120 mg daily) Primary outcome Percentage of patients experiencing 1 gout flare at week 49 to 72 43.5 % 43.5 https://web.pathway.md/studies/rec2OxYAeD8Pc5PwS 1/2 6/29/23, 11:57 PM STOP GOUT Pathway 3 5 36.5 32.6 % 21.8 % Difference not exceeding nonferiority margin 10.9 % 0.0 % Allopurinol Febuxostat Difference not exceeding nonferiority margin in the percentage of patients experiencing 1 gout flare at week 49 to 72 (36.5% vs. 43.5%; RR 0.84, 95% CI 0.34 to 1.34) Secondary outcomes No significant difference in the percentage of patients with serum urate levels below 6 mg/dL at week 25 to 48 (81.1% vs. 78.4%; RR 1.04, 95% CI 0.96 to 1.11) Significant decrease in the percentage of patients with CKD experiencing 1 gout flare at week 49 to 72 (31.9% vs. 45.3%; ARD -13.4, 95% CI -Infinity to -3.9) Safety outcomes No significant differences in death, serious adverse events, or cardiovascular events. Conclusion In patients with gout and hyperuricemia, allopurinol was noninferior to febuxostat with respect to the percentage of patients experiencing 1 gout flare at week 49 to 72. Reference James R O'Dell, Mary T Brophy, Michael H Pillinger et al. Comparative Effectiveness of Allopurinol and Febuxostat in Gout Management. NEJM Evid. 2022 Mar;1(3):10.1056/evidoa2100028. Open reference URL https://web.pathway.md/studies/rec2OxYAeD8Pc5PwS 2/2

6/29/23, 11:56 PM STOP-ACEi Pathway Feedback Search Clinical Topics Home Studies STOP ACEi STOP ACEi Disease Chronic kidney disease Trial question What is the effect of discontinuation of renin-angiotensin system inhibitors in patients with advanced CKD? Study design Multi-center Open label RCT Population Characteristics of study participants 32.0% female N = 411 68.0% male 411 patients (130 female, 281 male) Inclusion criteria: adult patients with advanced and progressive CKD Key exclusion criteria: uncontrolled hypertension; history of myocardial infarction or stroke within the previous 3 months Interventions N=206 renin-angiotensin system inhibitor discontinuation (use of any guideline-recommended antihypertensive agent other than renin-angiotensin system inhibitors) N=205 renin-angiotensin system inhibitor continuation (renin-angiotensin system inhibitor with/without any other guideline-recommended antihypertensive agent) https://web.pathway.md/studies/recv0MfYu0pPyKuD6 1/2 6/29/23, 11:57 PM STOP-ACEi Pathway Primary outcome Estimated glomerular filtration rate at 3 years 13.3 13.3 12.6 10.0 6.7 3.3 No significant difference 0.0 Renin-angiotensin system inhibitor discontinuation Renin-angiotensin system inhibitor continuation No significant difference in eGFR at 3 years (12.6 vs. 13.3; AD -0.7, 95% CI -2.5 to 1) Secondary outcomes No significant difference in end-stage kidney disease or renal-replacement therapy (62% vs. 56%; HR 1.28, 95% CI 0.99 to 1.65) No significant difference in the percentage of patients experiencing > 50% decline in eGFR or initiation of renal-replacement therapy (68% vs. 63%; RR 1.07, 95% CI 0.94 to 1.22) No significant difference in death (10% vs. 11%; HR 0.85, 95% CI 0.46 to 1.57) Safety outcomes No significant difference in serious adverse events. Conclusion In adult patients with advanced and progressive CKD, renin-angiotensin system inhibitor discontinuation was not superior to renin-angiotensin system inhibitor continuation with respect to eGFR at 3 years. Reference Sunil Bhandari, Samir Mehta, Arif Khwaja et al. Renin-Angiotensin System Inhibition in Advanced Chronic Kidney Disease. N Engl J Med. 2022 Dec 1;387(22):2021-2032. Open reference URL https://web.pathway.md/studies/recv0MfYu0pPyKuD6 2/2

6/29/23, 11:56 PM STOP-HF Pathway Feedback Search Clinical Topics Home Studies STOP HF STOP HF Disease Heart failure Trial question What is the role of screening program using brain-type natriuretic peptide and collaborative care in patients with cardiovascular risk factors? Study design Multi-center Open label RCT Population Characteristics of study participants 55.0% female N = 1374 45.0% male 1374 patients (751 female, 623 male) Inclusion criteria: patients with cardiovascular risk factors Key exclusion criteria: refused to provide informed consent, LV systolic dysfunction, history of symptomatic HF, or diagnosis compromising survival Interventions N=697 screening with BNP (with BNP 50 pg/mL undergoing echocardiography plus collaborative care between their primary care physician and specialist cardiovascular service) N=677 no routine BNP screening (usual primary care) Primary outcome https://web.pathway.md/studies/recfHcacRjL8MEC8J 1/2 6/29/23, 11:57 PM STOP-HF Pathway LV dysfunction with or without heart failure 8.7 % 8.7 6.5 % 5.3 4.3 % Significant decrease 2.2 % NNT = 29 0.0 % Screening with BNP No routine BNP screening Significant decrease in LV dysfunction with or without HF (5.3% vs. 8.7%; OR 0.55, 95% CI 0.37 to 0.82) Secondary outcomes Significant decrease in emergency hospitalization for major cardiovascular events (per 1,000 patient-years) (22.3 vs. 40.4; IRR 0.6, 95% CI 0.45 to 0.81) Significant decrease in asymptomatic LV dysfunction (4.3% vs. 6.6%; OR 0.57, 95% CI 0.37 to 0.88) No significant difference in HF (1% vs. 2.1%; OR 0.48, 95% CI 0.2 to 1.2) Conclusion In patients with cardiovascular risk factors, screening with BNP was superior to no routine BNP screening with respect to LV dysfunction with or without HF. Reference Ledwidge M, Gallagher J, Conlon C et al. Natriuretic peptide-based screening and collaborative care for heart failure: the STOP-HF randomized trial. JAMA. 2013 Jul 3;310(1):66-74. Open reference URL https://web.pathway.md/studies/recfHcacRjL8MEC8J 2/2

6/29/23, 11:57 PM STOP-IT Pathway Feedback Search Clinical Topics Home Studies STOP IT STOP IT Disease Disease Disease Acute appendicitis Acute cholecystitis Acute dive Trial question What is the effect of fixed-duration antibiotic therapy in patients with intra-abdominal infections who had undergone an adequate source-control procedure? Study design Multi-center Open label RCT Population Characteristics of study participants 44.0% female N = 518 56.0% male 518 patients (229 female, 289 male) Inclusion criteria: patients with complicated intra-abdominal infection and adequate source control Key exclusion criteria: age < 16 years; lack of adequate source control; high likelihood of death or lack of any clinical improvement within 72 hours of initial intervention; planned relaparotomy; perforated gastric ulcer or duodenal ulcer treated within 24 hours of the onset of symptoms Interventions N=258 experimental (receipt of a fixed course of antibiotics for 4 1 calendar days) N=260 control (receipt of antibiotics until 2 days after the resolution of fever, leukocytosis, and ileus, with a maximum of 10 days of therapy) https://web.pathway.md/studies/reca8CCLaWV81e5sS 1/2 6/29/23, 11:57 PM STOP-IT Pathway Primary outcome Rate of composite of surgical site infection, recurrent intra-abdominal infection, or death within 30 days after the index source-control procedure 22.3 % 22.3 21.8 16.7 % 11.2 % 5.6 % No significant difference 0.0 % Experimental Control No significant difference in the rate of composite of surgical site infection, recurrent intra-abdominal infection, or death within 30 days after the index source-control procedure (21.8% vs. 22.3%; ARD -0.5, 95% CI -7 to 8) Secondary outcomes Significant decrease in duration of therapy (4 days vs. 8 days; AD -4 days, 95% CI -4.7 to -3.3) No significant difference in death (1.2% vs. 0.8%; AD 0.4%, 95% CI -1.7 to 2.7) No significant difference in recurrent intra-abdominal infection (15.6% vs. 13.8%; AD 1.8%, 95% CI -4.5 to 7.8) Safety outcomes No significant differences in rates of extra-abdominal infection, C. difficile infection, secondary infections with resistant pathogens. Significant difference in antimicrobial free days at 30 days (25 days vs. 21 days). Conclusion In patients with complicated intra-abdominal infection and adequate source control, experimental was equivalent to control with respect to the rate of composite of surgical site infection, recurrent intra-abdominal infection, or death within 30 days after the index source-control procedure. Reference Robert G Sawyer, Jeffrey A Claridge, Avery B Nathens et al. Trial of short-course antimicrobial therapy for intraabdominal infection. N Engl J Med. 2015 May 21;372(21):1996-2005. Open reference URL https://web.pathway.md/studies/reca8CCLaWV81e5sS 2/2

6/29/23, 11:56 PM STOPDAPT-2 ACS Pathway Feedback Search Clinical Topics Home Studies STOPDAPT 2 ACS STOPDAPT 2 ACS Disease Disease Non-ST-elevation myocardial inf ST-elevation myocardial infarction Trial question Is clopidogrel monotherapy after 1-2 months of dual antiplatelet therapy noninferior to 12 months of dual antiplatelet therapy in patients with acute coronary syndrome? Study design Multi-center Open label RCT Population Characteristics of study participants 21.0% female N = 4136 79.0% male 4136 patients (856 female, 3280 male) Inclusion criteria: patients with acute coronary syndrome who underwent successful PCI Key exclusion criteria: requirement of OACs; medical history of intracranial hemorrhage; serious complications after PCI; intolerance to clopidogrel Interventions N=2078 short dual antiplatelet therapy (1-2 months of dual antiplatelet therapy followed by clopidogrel monotherapy) N=2091 long dual antiplatelet therapy (12 months of dual antiplatelet therapy with aspirin and clopidogrel) https://web.pathway.md/studies/reccRZ1Q7D6z98Xdn 1/2 6/29/23, 11:57 PM STOPDAPT-2 ACS Pathway Primary outcome Composite outcome of cardiovascular death, myocardial infarction, stent thrombosis, stroke, or bleeding 3.2 % 3.2 2.8 2.4 % 1.6 % Difference exceeding nonferiority margin 0.8 % 0.0 % Short dual antiplatelet therapy Long dual antiplatelet therapy Difference exceeding nonferiority margin in composite outcome of cardiovascular death, myocardial infarction, stent thrombosis, stroke, or bleeding (3.2% vs. 2.8%; HR 1.14, 95% CI 0.8 to 1.62) Secondary outcomes No significant difference in composite outcome of cardiovascular death, myocardial infarction, stent thrombosis, or stroke (2.8% vs. 1.9%; HR 1.5, 95% CI 0.99 to 2.26) Borderline significant decrease in bleeding (0.5% vs. 1.2%; HR 0.46, 95% CI 0.23 to 0.94) No significant difference in death from any cause (1.4% vs. 0.9%; HR 1.49, 95% CI 0.83 to 2.67) Conclusion In patients with acute coronary syndrome who underwent successful PCI, short dual antiplatelet therapy was not noninferior to long dual antiplatelet therapy with respect to the composite outcome of cardiovascular death, myocardial infarction, stent thrombosis, stroke, or bleeding. Reference Hirotoshi Watanabe, Takeshi Morimoto, Masahiro Natsuaki et al. Comparison of Clopidogrel Monotherapy After 1 to 2 Months of Dual Antiplatelet Therapy With 12 Months of Dual Antiplatelet Therapy in Patients With Acute Coronary Syndrome: The STOPDAPT-2 ACS Randomized Clinical Trial. JAMA Cardiol. 2022 Mar 2;e215244. Open reference URL https://web.pathway.md/studies/reccRZ1Q7D6z98Xdn 2/2

6/29/23, 11:57 PM Stopping Statins at the End of Life Pathway Feedback Search Clinical Topics Home Studies Stopping Statins at the End of Life Stopping Statins at the End of Life DiseaseDyslipidemia Trial question What is the role of discontinuation of statin therapy in patients with limited life expectancy? Study design Multi-center Open label RCT Population Characteristics of study participants 45.0% female N = 381 55.0% male 381 patients (171 female, 210 male) Inclusion criteria: adults with an estimated life expectancy of 1 month to 1 year, statin therapy for 3 months for primary or secondary prevention of CVD Key exclusion criteria: active CVD, symptoms of myositis, liver function test (AST, ALT, or ALP) or CK levels > 2.5 times the ULN, or other contraindications to continuing statin therapy Interventions N=189 discontinuation of statins (statin therapy withdrawn) N=192 continuation of statins (continued to receive statin therapy) Primary outcome Death at 60 days https://web.pathway.md/studies/recz1IzKpDVLg0S8t 1/2 6/29/23, 11:57 PM Stopping Statins at the End of Life Pathway 23.8 % 23.8 20.3 17.9 % 11.9 % Difference not exceeding nonferiority margin 6.0 % 0.0 % Discontinuation of statins Continuation of statins Difference not exceeding nonferiority margin in death at 60 days (23.8% vs. 20.3%; RR 1.17, 90% CI -3.5 to 10.5) Secondary outcomes Significant increase in total quality of life McGill QOL score (7.11 vs. 6.85; AD 0.26, 95% CI 0.02 to 0.5) No significant difference in cardiovascular events (6.9 vs. 5.7; RR 1.21, 95% CI -3.67 to 6.09) No significant difference in median time to death (229 days vs. 190 days; MD 39, 95% CI -102.05 to 180.05) Conclusion In adults with an estimated life expectancy of 1 month to 1 year, statin therapy for 3 months for primary or secondary prevention of CVD, discontinuation of statins were noninferior to continuation of statins with respect to death at 60 days. Reference Kutner JS, Blatchford PJ, Taylor DH Jr et al. Safety and benefit of discontinuing statin therapy in the setting of advanced, life-limiting illness: a randomized clinical trial. JAMA Intern Med. 2015 May;175(5):691-700. Open reference URL https://web.pathway.md/studies/recz1IzKpDVLg0S8t 2/2

6/29/23, 11:57 PM STORM Pathway Feedback Search Clinical Topics Home Studies STORM STORM Disease Hepatocellular carcinoma Trial question What is the role of adjuvant sorafenib in patients with HCC following resection or ablation? Study design Multi-center Double blinded RCT Population Characteristics of study participants 18.0% female N = 1114 82.0% male 1114 patients (202 female, 912 male) Inclusion criteria: patients with HCC with a complete radiological response after surgical resection or local ablation Key exclusion criteria: recurrent HCC; macrovascular invasion; CVD; infection with human immunodeficiency virus or other clinically serious infections; seizure disorder requiring drugs; previous anticancer treatment for HCC Interventions N=556 sorafenib (at an oral dose of 400 mg BID, for a maximum of 4 years) N=558 placebo (matching placebo BID, for a maximum of 4 years) Primary outcome https://web.pathway.md/studies/rec5NOqYclIxQWr4H 1/2 6/29/23, 11:57 PM STORM Pathway Median recurrence-free survival 33.7 months 33.7 33.3 25.3 months 16.9 months 8.4 months No significant difference 0.0 months Sorafenib Placebo No significant difference in median recurrence-free survival (33.3 months vs. 33.7 months; HR 0.94, 95% CI 0.78 to 1.13) Secondary outcomes No significant difference in median time to recurrence (38.5 months vs. 35.8 months; HR 0.891, 95% CI 0.73 to 1.08) Safety outcomes No significant difference in any adverse event. Significant differences in drug-related adverse events (94% vs. 46%), grade 3 or 4 hand-foot skin reaction (28% vs. <1%). Conclusion In patients with HCC with a complete radiological response after surgical resection or local ablation, sorafenib was not superior to placebo with respect to median recurrence-free survival. Reference Jordi Bruix, Tadatoshi Takayama, Vincenzo Mazzaferro et al. Adjuvant sorafenib for hepatocellular carcinoma after resection or ablation (STORM): a phase 3, randomised, double-blind, placebo- controlled trial. Lancet Oncol. 2015 Oct;16(13):1344-54. Open reference URL https://web.pathway.md/studies/rec5NOqYclIxQWr4H 2/2

6/29/23, 11:57 PM STRIDE Pathway Feedback Search Clinical Topics Home Studies STRIDE STRIDE Disease Falls in the elderly Trial question What is the effect of implementation of a supervised walking program in hospitalized community- dwelling older adults? Study design Multi-center Open label RCT Population Characteristics of study participants 3.0% female N = 12863 97.0% male 12863 patients (521 female, 16716 male) Inclusion criteria: adults patients 60 years of age who were community-dwelling and hospitalized for 2 days Key exclusion criteria: index hospital stay < 2 business days; current hospitalization; current high- risk suicide flag in medical record; diagnosis of cognitive impairment or dementia Interventions N=6722 STRIDE (implementation of a supervised walking program known as assisted early mobility for hospitalized veterans) N=6141 usual care (pre-implementation before STRIDE program) https://web.pathway.md/studies/rectEgwqbphX8p3k9 1/2 6/29/23, 11:57 PM STRIDE Pathway Primary outcome Discharge to a skilled nursing facility 13.0 % 13 9.8 % 8 6.5 % 3.3 % Borderline significant decrease 0.0 % STRIDE Usual care Borderline significant decrease in discharge to a skilled nursing facility (8% vs. 13%; OR 0.6, 95% CI 0.5 to 0.8) Secondary outcomes No significant difference in length of hospital stay (6.92 days vs. 6.58 days; RR 1.05, 95% CI 0.97 to 1.15) No significant difference in physical function-disability, measured by Late Life Function and Disability Instrument (67.31 vs. 65.99; MD 1.32, 95% CI -2.7 to 5.33) No significant difference in physical function-limitations, measured by Late Life Function and Disability Instrument (65.67 vs. 64.12; MD 1.56, 95% CI -3.14 to 6.25) Conclusion In adults patients 60 years of age who were community-dwelling and hospitalized for 2 days, STRIDE was superior to usual care with respect to discharge to a skilled nursing facility. Reference Susan N Hastings, Karen M Stechuchak, Ashley Choate et al. Effects of Implementation of a Supervised Walking Program in Veterans Affairs Hospitals : A Stepped-Wedge, Cluster Randomized Trial. Ann Intern Med. 2023 Jun 6. Online ahead of print. Open reference URL https://web.pathway.md/studies/rectEgwqbphX8p3k9 2/2

6/29/23, 11:57 PM STRIVE Pathway Feedback Search Clinical Topics Home Studies STRIVE STRIVE Disease Disease Low back pain Surgical site infection Trial question What is the effect of a four-antigen S. aureus vaccine in patients undergoing elective spinal fusion surgical procedures? Study design Multi-center Double blinded RCT Population Characteristics of study participants 55.0% female N = 3450 45.0% male 3450 patients (1907 female, 1543 male) Inclusion criteria: patients aged 18-85 years scheduled to undergo elective spinal fusion surgical procedures Key exclusion criteria: surgical indication of malignancy; infection, or acute or emergency trauma; major surgery within 3 months prior to enrolment; spinal surgery performed within 6 months prior to study enrolment; congenital or acquired immunodeficiency disorder Interventions N=1726 S. aureus four-antigen vaccine (four-antigen S. aureus vaccine 10-60 days before surgery) N=1724 placebo (sterile water injection 10-60 days before surgery) https://web.pathway.md/studies/recRwFHoTCFe5I85z 1/2 6/29/23, 11:57 PM STRIVE Pathway Primary outcome Staphylococcus aureus blood stream infection 0.7 % 0.7 0.5 % 0.5 0.3 % 0.2 % No significant difference 0.0 % Staphylococcus aureus four-antigen vaccine Placebo No significant difference in S. aureus blood stream infection (0.5% vs. 0.7%; AD -0.2%, 95% CI -0.4 to 0) Secondary outcomes No significant difference in S. aureus surgical site infection (1.6% vs. 1.4%; AD 0.2%, 95% CI -0.37 to 0.77) Safety outcomes No significant differences in adverse events, systemic events. Conclusion In patients aged 18-85 years scheduled to undergo elective spinal fusion surgical procedures, S. aureus four-antigen vaccine was not superior to placebo with respect to S. aureus blood stream infection. Reference Hamid Hassanzadeh, James Baber, Elizabeth Begier et al. Efficacy of a 4-Antigen Staphylococcus aureus Vaccine in Spinal Surgery: The STRIVE Randomized Clinical Trial. Clin Infect Dis. 2023 May 1;ciad218. Open reference URL https://web.pathway.md/studies/recRwFHoTCFe5I85z 2/2

6/29/23, 11:57 PM STRONG-HF Pathway Feedback Search Clinical Topics Home Studies STRONG HF STRONG HF Disease Heart failure Trial question What is the role of up-titration of guideline-directed medical therapies in patients with acute HF? Study design Multi-center Open label RCT Population Characteristics of study participants 39.0% female N = 1078 61.0% male 1078 patients (416 female, 662 male) Inclusion criteria: patients aged 18-85 years admitted to hospital with acute HF, not treated with full doses of guideline-directed drug treatment Key exclusion criteria: age < 18 or > 85 years; intolerance to high doses of -blockers and renin- angiotensin system blockers; mechanical ventilation in the 24 hours prior to screening Interventions N=542 high-intensity care (rapid up-titration of guideline-directed drug treatments to 100% of recommended doses and close follow-up) N=536 usual care (usual local practice) Primary outcome https://web.pathway.md/studies/rectdFfuNTIdLCaLD 1/2 6/29/23, 11:57 PM STRONG-HF Pathway Readmission to hospital due to heart failure or death at day 180 23.3 % 23.3 17.5 % 15.2 11.7 % Significant decrease 5.8 % NNT = 12 0.0 % High-intensity care Usual care Significant decrease in readmission to hospital due to HF or death at day 180 (15.2% vs. 23.3%; RR 0.66, 95% CI 0.5 to 0.86) Secondary outcomes Significant increase in elevation in the EuroQol VAS at 12 months (10.72 vs. 7.22; AD 3.49, 95% CI 1.74 to 5.24) Significant increase in death from all causes at day 180 (8.5% vs. 10%; AD 1.6%, 95% CI 0.56 to 1.26) Safety outcomes No significant difference in serious adverse events and fatal adverse events. Significant difference in adverse events by day 90 (41% vs. 29%). Conclusion In patients aged 18-85 years admitted to hospital with acute HF, not treated with full doses of guideline-directed drug treatment, high-intensity care was superior to usual care with respect to readmission to hospital due to HF or death at day 180. Reference Alexandre Mebazaa, Beth Davison, Ovidiu Chioncel et al. Safety, tolerability and efficacy of up- titration of guideline-directed medical therapies for acute heart failure (STRONG-HF): a multinational, open-label, randomised, trial. Lancet. 2022 Dec 3;400(10367):1938-1952. Open reference URL https://web.pathway.md/studies/rectdFfuNTIdLCaLD 2/2

6/29/23, 11:57 PM Sub-Threshold Exercise for SRC Pathway Feedback Search Clinical Topics Home Studies Sub-Threshold Exercise for SRC Sub-Threshold Exercise for SRC Disease Concussion Trial question What is the effect of early subsymptom threshold aerobic exercise treatment in adolescents with sport-related concussion? Study design Multi-center Open label RCT Population Characteristics of study participants 47.0% female N = 103 53.0% male 103 patients (48 female, 55 male) Inclusion criteria: adolescent athletes, aged 13-18 years, presenting within 10 days of sport- related concussion Key exclusion criteria: evidence of focal neurological deficit; inability to exercise because of orthopedic injury, cervical spine injury, diabetes, or known heart disease; increased cardiac risk according to american college of sports medicine criteria; history of moderate-severe TBI Interventions N=52 aerobic exercise (prescription to exercise at 80% of their threshold HR for symptom exacerbation) N=51 stretching exercise (prescription for daily stretching lasting approximately 20 minutes) https://web.pathway.md/studies/recavRQSVi3rPjaQ5 1/2 6/29/23, 11:57 PM Sub-Threshold Exercise for SRC Pathway Primary outcome Median recovery time 17.0 days 17 13 12.8 days 8.5 days 4.3 days Significant decrease 0.0 days Aerobic exercise Stretching exercise Significant decrease in median recovery time (13 days vs. 17 days; AD -4 days, 95% CI -7 to -1) Secondary outcomes No significant difference in delayed recovery since injury (4% vs. 14%; ARD -10, 95% CI -21.21 to 1.21) No significant difference in daily symptom reporting (83.8% vs. 86.6%; RR 0.97, 95% CI -0.38 to 2.32) Conclusion In adolescent athletes, aged 13-18 years, presenting within 10 days of sport-related concussion, aerobic exercise was superior to stretching exercise with respect to median recovery time. Reference John J Leddy, Mohammad N Haider, Michael J Ellis et al. Early Subthreshold Aerobic Exercise for Sport-Related Concussion: A Randomized Clinical Trial. JAMA Pediatr. 2019 Apr 1;173(4):319-325. Open reference URL https://web.pathway.md/studies/recavRQSVi3rPjaQ5 2/2

6/29/23, 11:57 PM Subira Pathway Feedback Search Clinical Topics Home Studies Subira Subira Trial question What is the effect of spontaneous breathing trial of pressure support ventilation strategy among patients receiving mechanical ventilation? Study design Multi-center Open label RCT Population Characteristics of study participants 37.0% female N = 1153 63.0% male 1153 patients (428 female, 725 male) Inclusion criteria: adult patients deemed ready for weaning after at least 24 hours of mechanical ventilation Key exclusion criteria: tracheostomies or do-not-reintubate orders Interventions N=575 a pressure support ventilation strategy (a 30-minute spontaneous breathing trial with 8- cmH O pressure support ventilation) N=578 a T-piece ventilation strategy (2 hours of T-piece spontaneous breathing trial) Primary outcome Successful extubation 82.3 % 82.3 74 61.7 % 41.1 % Significant increase 20.6 % https://web.pathway.md/studies/recgPJ52envfElEm8 1/2 6/29/23, 11:57 PM Subira Pathway NNT = 12 0.0 % A pressure support ventilation strategy A T-piece ventilation strategy Significant increase in successful extubation (82.3% vs. 74%; AD 8.2%, 95% CI 3.4 to 13) Secondary outcomes No significant difference in reintubation (11.1% vs. 11.9%; ARD -0.8, 95% CI -4.8 to 3.1) No significant difference in ICU length of stay (9 days vs. 10 days; AD -0.3 days, 95% CI -1.7 to 1.1) Significant decrease in death at 90 days (13.2% vs. 17.3%; HR 0.74, 95% CI 0.55 to 0.99) Safety outcomes No significant differences in hemodynamic shock, agitation, airway obstruction, difficulty managing secretions. Significant differences in death in the hospital (10.4% vs. 14.9%), aspiration (1.7% vs. 5.2%), cardiac arrest (1.7% vs. 5.1%). Conclusion In adult patients deemed ready for weaning after at least 24 hours of mechanical ventilation, a pressure support ventilation strategy was superior to a T-piece ventilation strategy with respect to successful extubation. Reference Carles Subir , Gonzalo Hern ndez, Ant nia V zquez et al. Effect of Pressure Support vs T-Piece Ventilation Strategies During Spontaneous Breathing Trials on Successful Extubation Among Patients Receiving Mechanical Ventilation: A Randomized Clinical Trial. JAMA. 2019 Jun 11;321(22):2175-2182. Open reference URL https://web.pathway.md/studies/recgPJ52envfElEm8 2/2

6/29/23, 11:57 PM SUP-ICU Pathway Feedback Search Clinical Topics Home Studies SUP ICU SUP ICU Disease Disease Disease Lower gastrointestinal bleeding Non-variceal upper gastrointesti Variceal h Trial question What is the role of pantoprazole in patients at risk for gastrointestinal bleeding in the ICU? Study design Multi-center Double blinded RCT Population Characteristics of study participants 36.0% female N = 3298 64.0% male 3298 patients (1185 female, 2106 male) Inclusion criteria: adults admitted to the ICU for an acute condition who were at risk for gastrointestinal bleeding Key exclusion criteria: ongoing daily treatment with acid suppressants, gastrointestinal bleeding during index hospital admission, withdrawn from active therapy or brain dead, organ transplantation during index hospital admission, peptic ulcer, contraindication to pantoprazole, pregnant Interventions N=1645 pantoprazole (intravenous injection of 40 mg suspended in 10 ml of 0.9% sodium chloride daily for a maximum of 90 days) https://web.pathway.md/studies/recfwufeSkj58BX5P 1/2 6/29/23, 11:57 PM SUP-ICU Pathway N=1653 placebo (intravenous injection of matching placebo suspended in 10 ml of 0.9% sodium chloride daily for a maximum of 90 days) Primary outcome Death at 90 days 31.1 % 31.1 30.4 23.3 % 15.6 % 7.8 % No significant difference 0.0 % Pantoprazole Placebo No significant difference in death at 90 days (31.1% vs. 30.4%; RR 1.02, 95% CI 0.91 to 1.13) Secondary outcomes No significant difference in clinically important gastrointestinal bleeding, pneumonia, C. difficile infection, or myocardial ischemia, during the ICU stay (21.9% vs. 22.6%; RR 0.96, 96% CI 0.83 to 1.11) Safety outcomes No significant differences in serious adverse reactions, number of patients with infections and the percentage of days alive without life support within 90 days. Conclusion In adults admitted to the ICU for an acute condition who were at risk for gastrointestinal bleeding, pantoprazole was not superior to placebo with respect to death at 90 days. Reference Krag M, Marker S, Perner A et al. Pantoprazole in Patients at Risk for Gastrointestinal Bleeding in the ICU. N Engl J Med. 2018 Dec 6;379(23):2199-2208. Open reference URL https://web.pathway.md/studies/recfwufeSkj58BX5P 2/2

6/29/23, 11:57 PM SUPPORT Pathway Feedback Search Clinical Topics Home Studies SUPPORT SUPPORT Trial question What is the role of right heart catheterization in the initial care of critically ill patients? Study design Multi-center Open label Observational study Population Characteristics of study participants 44.0% female N = 5735 56.0% male 5735 patients (2543 female, 3192 male) Inclusion criteria: critically ill adult patients receiving care in an ICU Key exclusion criteria: age < 18 years; death or discharge in < 48 hours; acute psychiatric disorders; pregnancy; AIDS; acute burns; head trauma Interventions N=2184 right heart catheterization (performed within 24 hours of study entry) N=3551 no right heart catheterization (standard of care without right heart catheterization) Primary outcome Survival at day 30 69.4 % 69.4 62 52.1 % 34.7 % Significant decrease 17.4 % NNH = 14 0.0 % https://web.pathway.md/studies/recW6YY9FYnTRUkXt 1/2 6/29/23, 11:57 PM SUPPORT Pathway Right heart catheterization No right heart catheterization Significant decrease in survival at day 30 (62% vs. 69.4%; ARD -7.4, 95% CI -11.79 to -3.01) Secondary outcomes Significant decrease in survival at 2 months (54.5% vs. 62.8%; ARD -8.3, 95% CI -13.22 to -3.38) Significant decrease in survival at 6 months (46.3% vs. 53.7%; ARD -7.4, 95% CI -11.79 to -3.01) Significant increase in length of stay in the ICU (15.5 days vs. 10.3 days; AD 5.2 days, 95% CI 2.11 to 8.29) Conclusion In critically ill adult patients receiving care in an ICU, right heart catheterization was inferior to no right heart catheterization with respect to survival at day 30. Reference A F Connors Jr, T Speroff, N V Dawson et al. The effectiveness of right heart catheterization in the initial care of critically ill patients. SUPPORT Investigators. JAMA. 1996 Sep 18;276(11):889-97. Open reference URL https://web.pathway.md/studies/recW6YY9FYnTRUkXt 2/2

6/29/23, 11:57 PM SURMOUNT-1 (high-dose) Pathway Feedback Search Clinical Topics Home Studies SURMOUNT 1 (high-dose) SURMOUNT 1 (high-dose) Disease Obesity Trial question What is the role of a high dose of tirzepatide in people with obesity? Study design Multi-center Double blinded RCT Population Characteristics of study participants 68.0% female N = 1273 32.0% male 1273 patients (861 female, 412 male) Inclusion criteria: adults with a BMI > 30, or > 27 and at least one weight-related complication, excluding diabetes Key exclusion criteria: diabetes; a change in body weight > 5 kg within 90 days before screening; previous or planned surgical treatment for obesity; treatment with a medication that promotes weight loss within 90 days before screening Interventions N=630 high-dose tirzepatide (a subcutaneous dose of 15 mg once weekly for 72 weeks) N=643 placebo (matching placebo once-weekly) Primary outcome https://web.pathway.md/studies/rec4enXnXQc74FNN1 1/2 6/29/23, 11:57 PM SURMOUNT-1 (high-dose) Pathway Weight reduction at week 72 20.9 % 20.9 15.7 % 10.4 % Significant increase 5.2 % NNT = 6 3.1 0.0 % High-dose tirzepatide Placebo Significant increase in weight reduction at week 72 (20.9% vs. 3.1%; AD 17.8%, 95% CI 16.3 to 19.3) Secondary outcomes Significant increase in the percentage of patients achieving a weight reduction of 5% at week 72 (90.9% vs. 34.5%; AD 56.4%, 95% CI 22.93 to 89.87) Significant increase in the percentage of patients achieving a weight reduction of 10% at week 72 (83.5% vs. 18.8%; AD 64.7%, 95% CI 26.31 to 103.09) Significant increase in reduction in waist circumference (18.5 cm vs. 4 cm; AD 14.5 cm, 95% CI 5.9 to 23.1) Safety outcomes No significant difference in serious adverse events. Conclusion In adults with a BMI > 30, or > 27 and at least one weight-related complication, excluding diabetes, high-dose tirzepatide was superior to placebo with respect to weight reduction at week 72. Reference Ania M Jastreboff, Louis J Aronne, Nadia N Ahmad et al. Tirzepatide Once Weekly for the Treatment of Obesity. N Engl J Med. 2022 Jul 21;387(3):205-216. Open reference URL https://web.pathway.md/studies/rec4enXnXQc74FNN1 2/2

6/29/23, 11:57 PM SURMOUNT-1 (low-dose) Pathway Feedback Search Clinical Topics Home Studies SURMOUNT 1 (low-dose) SURMOUNT 1 (low-dose) Disease Obesity Trial question What is the role of a low dose of tirzepatide in people with obesity? Study design Multi-center Double blinded RCT Population Characteristics of study participants 68.0% female N = 1273 32.0% male 1273 patients (862 female, 411 male) Inclusion criteria: adults with a BMI > 30, or > 27 and at least one weight-related complication, excluding diabetes Key exclusion criteria: diabetes; a change in body weight > 5 kg within 90 days before screening; previous or planned surgical treatment for obesity; treatment with a medication that promotes weight loss within 90 days before screening Interventions N=630 low-dose of tirzepatide (a subcutaneous dose of 5 mg once weekly for 72 weeks) N=643 placebo (matching placebo once-weekly) Primary outcome https://web.pathway.md/studies/rec1AwLkzb1EjQ296 1/2 6/29/23, 11:57 PM SURMOUNT-1 (low-dose) Pathway Weight reduction at week 72 15.0 % 15 11.3 % 7.5 % Significant increase 3.8 % NNT = 8 3.1 0.0 % Low-dose of tirzepatide Placebo Significant increase in weight reduction at week 72 (15% vs. 3.1%; AD 11.9%, 95% CI 10.4 to 13.4) Secondary outcomes Significant increase in the percentage of patients achieving a weight reduction of 5% at week 72 (85.1% vs. 34.5%; AD 50.6%, 95% CI 20.58 to 80.62) Significant increase in the percentage of patients achieving a weight reduction of 10% at week 72 (68.5% vs. 18.8%; AD 49.7%, 95% CI 20.21 to 79.19) Significant increase in reduction in waist circumference (14 cm vs. 4 cm; AD 10.1 cm, 95% CI 4.11 to 16.09) Safety outcomes No significant difference in serious adverse events. Conclusion In adults with a BMI > 30, or > 27 and at least one weight-related complication, excluding diabetes, low-dose of tirzepatide was superior to placebo with respect to weight reduction at week 72. Reference Ania M Jastreboff, Louis J Aronne, Nadia N Ahmad et al. Tirzepatide Once Weekly for the Treatment of Obesity. N Engl J Med. 2022 Jul 21;387(3):205-216. Open reference URL https://web.pathway.md/studies/rec1AwLkzb1EjQ296 2/2

6/29/23, 11:57 PM SURMOUNT-1 (mid-dose) Pathway Feedback Search Clinical Topics Home Studies SURMOUNT 1 (mid-dose) SURMOUNT 1 (mid-dose) Disease Obesity Trial question What is the role of a mid-dose of tirzepatide in adults with obesity? Study design Multi-center Double blinded RCT Population Characteristics of study participants 67.0% female N = 1279 33.0% male 1279 patients (863 female, 416 male) Inclusion criteria: adults with a BMI > 30, or > 27 and at least one weight-related complication, excluding diabetes Key exclusion criteria: diabetes; a change in body weight > 5 kg within 90 days before screening; previous or planned surgical treatment for obesity; treatment with a medication that promotes weight loss within 90 days before screening Interventions N=636 mid-dose of tirzepatide (a subcutaneous dose of 10 mg once weekly for 72 weeks) N=643 placebo (matching placebo once-weekly) Primary outcome https://web.pathway.md/studies/reclUVk0iZdXENScs 1/2 6/29/23, 11:57 PM SURMOUNT-1 (mid-dose) Pathway Weight reduction at week 72 19.5 % 19.5 14.6 % 9.8 % Significant increase 4.9 % NNT = 6 3.1 0.0 % Mid-dose of tirzepatide Placebo Significant increase in weight reduction at week 72 (19.5% vs. 3.1%; AD 16.4%, 95% CI 14.8 to 17.9) Secondary outcomes Significant increase in the percentage of patients achieving a weight reduction of 5% at week 72 (88.9% vs. 34.5%; AD 54.4%, 95% CI 22.12 to 86.68) Significant increase in the percentage of patients achieving a weight reduction of 10% at week 72 (78.1% vs. 18.8%; AD 59.3%, 95% CI 24.11 to 94.49) Significant increase in reduction in waist circumference (17.7 cm vs. 4 cm; AD 13.8 cm, 95% CI 12.3 to 15.2) Safety outcomes No significant difference in serious adverse events. Conclusion In adults with a BMI > 30, or > 27 and at least one weight-related complication, excluding diabetes, mid-dose of tirzepatide was superior to placebo with respect to weight reduction at week 72. Reference Ania M Jastreboff, Louis J Aronne, Nadia N Ahmad et al. Tirzepatide Once Weekly for the Treatment of Obesity. N Engl J Med. 2022 Jul 21;387(3):205-216. Open reference URL https://web.pathway.md/studies/reclUVk0iZdXENScs 2/2

6/29/23, 11:57 PM SURPASS-4 (post-hoc analysis) Pathway Feedback Search Clinical Topics Home Studies SURPASS 4 (post-hoc analysis) SURPASS 4 (post-hoc analysis) Disease Diabetes mellitus type 2 Trial question Is tirzepatide superior to insulin glargine in patients with T2DM with regard to renal outcomes? Study design Multi-center Open label RCT Population 1995 patients Inclusion criteria: adults with inadequately controlled T2DM on oral diabetes medication and high cardiovascular risk Key exclusion criteria: T1DM mellitus, chronic or acute pancreatitis, acute or chronic hepatitis, diabetic retinopathy requiring urgent treatment, heart attack or stroke in the past 2 months Interventions N=995 tirzepatide (once-weekly subcutaneous injection at a dose of 5 mg, 10 mg, or 15 mg) N=1000 insulin glargine (once-daily subcutaneous injection titrated to 100 U/mL) Primary outcome Estimated glomerular filtration decline 3.6 mL/min/1.73m 3.6 2.7 mL/min/1.73m 1.8 mL/min/1.73m 1.4 0.9 mL/min/1.73m https://web.pathway.md/studies/recoQgT4uDNUJH5wO 1/2 6/29/23, 11:57 PM SURPASS-4 (post-hoc analysis) Pathway Significant decrease 0.0 mL/min/1.73m Tirzepatide Insulin glargine Significant decrease in estimated glomerular filtration decline (1.4 mL/min/1.73 m vs. 3.6 mL/min/1.73 m ; AD -2.2 mL/min/1.73 m , 95% CI -1.6 to -2.8) Secondary outcomes Significant increase in urine albumin-creatinine ratio reduction (6.8% vs. -36.9%; AD 31.9%, 95% CI 25.7 to 37.7) Conclusion In adults with inadequately controlled T2DM on oral diabetes medication and high cardiovascular risk, tirzepatide was superior to insulin glargine with respect to estimated glomerular filtration decline. Reference Hiddo J L Heerspink, Naveed Sattar, Imre Pavo et al. Effects of tirzepatide versus insulin glargine on kidney outcomes in type 2 diabetes in the SURPASS-4 trial: post-hoc analysis of an open-label, randomised, phase 3 trial. Lancet Diabetes Endocrinol. 2022 Sep 21;S2213-8587(22)00243-1. Open reference URL https://web.pathway.md/studies/recoQgT4uDNUJH5wO 2/2

6/29/23, 11:57 PM SURTAVI Pathway Feedback Search Clinical Topics Home Studies SURTAVI SURTAVI Disease Aortic stenosis Trial question Is TAVR noninferior to SAVR in patients with severe aortic stenosis who are at intermediate surgical risk? Study design Multi-center Open label RCT Population Characteristics of study participants 43.2% female N = 1746 56.8% male 1746 patients (724 female, 936 male) Inclusion criteria: patients with symptomatic, severe aortic stenosis who are at intermediate surgical risk Key exclusion criteria: refusal for SAVR as a treatment option, contraindication for placement of a bioprosthetic valve, known hypersensitivity or contraindication to all anticoagulation/antiplatelet regimens, blood dyscrasias, ongoing sepsis, contraindication to extracorporeal assistance, cardiogenic shock or symptomatic carotid or vertebral artery disease Interventions N=864 TAVR (with the use of a self-expanding bioprosthesis) N=796 SAVR (surgical bioprosthesis) https://web.pathway.md/studies/recaUUGRhLehIP2n2 1/2 6/29/23, 11:57 PM SURTAVI Pathway Primary outcome Death or disabling stroke at 24 months 14.0 % 14 12.6 10.5 % 7.0 % Difference not exceeding nonferiority margin 3.5 % 0.0 % Transcatheter aortic valve replacement Surgical aortic valve replacement Difference not exceeding nonferiority margin in death or disabling stroke at 24 months (12.6% vs. 14%; ARD -1.4, 95% CI -5.2 to 2.3) Secondary outcomes No significant difference in death from any cause at 2 years (11.4% vs. 11.6%; ARD -0.2, 95% CI -3.8 to 3.3) Safety outcomes Significant differences in early ( 30 day) AKI stage 2 or 3, new or worsening AF, and the need for transfusion (more common in surgery group) and major vascular complications and the need for permanent pacemaker implantation (more common in TAVR group). Conclusion In patients with symptomatic, severe aortic stenosis who are at intermediate surgical risk, TAVR was noninferior to SAVR with respect to death or disabling stroke at 24 months. Reference Reardon MJ, Van Mieghem NM, Popma JJ et al. Surgical or Transcatheter Aortic-Valve Replacement in Intermediate-Risk Patients. N Engl J Med. 2017 Apr 6;376(14):1321-1331. Open reference URL https://web.pathway.md/studies/recaUUGRhLehIP2n2 2/2

6/29/23, 11:57 PM SUSTAIN-6 Pathway Feedback Search Clinical Topics Home Studies SUSTAIN 6 SUSTAIN 6 Disease Diabetes mellitus type 2 Reference Marso SP, Bain SC, Consoli A et al. Semaglutide and Cardiovascular Outcomes in Patients with Type 2 Diabetes. N Engl J Med. 2016 Nov 10;375(19):1834-1844. Open reference URL https://web.pathway.md/studies/recXLXOHktVwY415s 1/1

6/29/23, 11:57 PM SWOG 8949 Pathway Feedback Search Clinical Topics Home Studies SWOG 8949 SWOG 8949 Disease Renal cell carcinoma Trial question Is radical nephrectomy followed by therapy with interferon alfa-2b superior to interferon alfa-2b therapy alone in patients with metastatic renal cell cancer? Study design Multi-center Open label RCT Population Characteristics of study participants 30.6% female N = 246 69.4% male 246 patients (74 female, 167 male) Inclusion criteria: patients with metastatic renal cell cancer who were acceptable candidates for nephrectomy Key exclusion criteria: thrombosis of the IVC below the hepatic veins, uncontrolled cardiac arrhythmias, prior treatment with chemotherapy, hormonal therapy, interferon, or other biologic response modifiers, prior or concomitant radiation therapy to the primary tumor or to metastatic sites Interventions N=120 surgery plus interferon (immediate radical nephrectomy followed by therapy with interferon alfa-2b) https://web.pathway.md/studies/rec8EX6RZRGJLafFz 1/2 6/29/23, 11:57 PM SWOG 8949 Pathway N=121 interferon treatment alone (immediate interferon alfa-2b therapy without surgery) Primary outcome Survival 11.1 months 11.1 8.3 months 8.1 5.5 months 2.8 months No significant difference 0.0 months Surgery plus interferon Interferon treatment alone No significant difference in survival (11.1 months vs. 8.1 months; AD 3 months, 95% CI -0.01 to 6.01) Secondary outcomes No significant difference in survival with performance status 1 (6.9 months vs. 4.8 months; AD 2.1 months, 95% CI -0.25 to 4.45) Significant increase in survival with lung metastases (14.3 months vs. 10.3 months; AD 4 months, 95% CI 1.04 to 6.96) Conclusion In patients with metastatic renal cell cancer who were acceptable candidates for nephrectomy, surgery plus interferon was superior to interferon treatment alone with respect to survival. Reference Flanigan RC, Salmon SE, Blumenstein BA et al. Nephrectomy followed by interferon alfa-2b compared with interferon alfa-2b alone for metastatic renal-cell cancer. N Engl J Med. 2001 Dec 6;345(23):1655-9. Open reference URL https://web.pathway.md/studies/rec8EX6RZRGJLafFz 2/2

6/29/23, 11:57 PM SYGMA 2 Pathway Feedback Search Clinical Topics Home Studies SYGMA 2 SYGMA 2 Disease Asthma Trial question Is budesonide-formoterol noninferior to budesonide maintenance therapy in patients with mild asthma? Study design Multi-center Double blinded RCT Population Characteristics of study participants 62.6% female N = 4215 37.4% male 4215 patients (2597 female, 1579 male) Inclusion criteria: patients with mild asthma and were eligible for treatment with regular ICSs Key exclusion criteria: worsening asthma involving change in asthma treatment or the usee of systemic corticosteroids in the previous 30 days, current or former smoking with a history of 10 pack-years, and a history of life-threatening asthma Interventions N=2089 budesonide and formoterol (twice-daily placebo plus budesonide 200 g and formoterol 6 g used as needed) N=2087 budesonide maintenance (twice-daily budesonide 200 g plus terbutaline 0.5 mg as needed) https://web.pathway.md/studies/recGVelCQxKJKG12b 1/2 6/29/23, 11:57 PM SYGMA 2 Pathway Primary outcome Percentage of patients achieving an improvement in ACQ-5 score 44.3 % 44.3 40.3 33.2 % 22.1 % 11.1 % Borderline significant decrease 0.0 % Budesonide and formoterol Budesonide maintenance Borderline significant decrease in the percentage of patients achieving an improvement in ACQ-5 score (40.3% vs. 44.3%; OR 0.86, 95% CI 0.75 to 0.99) Safety outcomes No significant difference in adverse events. Conclusion In patients with mild asthma and were eligible for treatment with regular ICSs, budesonide and formoterol were noninferior to budesonide maintenance with respect to the percentage of patients achieving an improvement in ACQ-5 score. Reference Bateman ED, Reddel HK, O'Byrne PM et al. As-Needed Budesonide-Formoterol versus Maintenance Budesonide in Mild Asthma. N Engl J Med. 2018 May 17;378(20):1877-1887. Open reference URL https://web.pathway.md/studies/recGVelCQxKJKG12b 2/2

6/29/23, 11:57 PM Symptom-triggered vs. fixed-dose benzodiazepines for alcohol withdrawal Pathway Feedback Search Clinical Topics Home Studies Symptom-triggered vs. fixed-dose benzodiazepines for alcohol withdrawal Symptom-triggered vs. fixed-dose benzodiazepines for alcohol withdrawal Disease Alcohol use disorder Trial question Is symptom-triggered doses of benzodiazepine superior to fixed-schedule doses of benzodiazepine in patients with alcohol withdrawal? Study design Multi-center Double blinded RCT Population Characteristics of study participants 23.0% female N = 117 77.0% male 117 patients (27 female, 90 male) Inclusion criteria: patients with alcohol dependence entering an alcohol treatment program Key exclusion criteria: last alcoholic beverage intake > 72 hours prior to admission; daily use of medication for treatment of alcohol withdrawal for the 30 days prior to admission (ie, benzodiazepines, barbiturates, or clomethiazole); major cognitive, psychiatric, or medical comorbidity; opiate or stimulant dependence; and/or no fluency in French Interventions N=56 symptom-triggered benzodiazepine administration (oxazepam in response to the development of signs of alcohol withdrawal) https://web.pathway.md/studies/recfKpFpUS7ACpKIW 1/2 6/29/23, 11:57 PM Symptom-triggered vs. fixed-dose benzodiazepines for alcohol withdrawal Pathway N=61 fixed-schedule benzodiazepine administration (oxazepam every 6 hours with additional doses as needed) Primary outcome Total amount of oxazepam administered 231.4 mg 231.4 173.6 mg 115.7 mg 57.9 mg Significant decrease 37.5 0.0 mg Symptom-triggered benzodiazepine administration Fixed-schedule benzodiazepine administration Significant decrease in total amount of oxazepam administered (37.5 mg vs. 231.4 mg; ARD -193.9, 95% CI -308.95 to -78.85) Secondary outcomes Significant decrease in duration of treatment with oxazepam (20 hours vs. 62.7 hours; MD -42.7, 95% CI -68.04 to -17.36) Safety outcomes Significant difference in seizures (1 vs. 0). Conclusion In patients with alcohol dependence entering an alcohol treatment program, symptom-triggered benzodiazepine administration was superior to fixed-schedule benzodiazepine administration with respect to total amount of oxazepam administered. Reference Daeppen JB, Gache P, Landry U et al. Symptom-triggered vs fixed-schedule doses of benzodiazepine for alcohol withdrawal: a randomized treatment trial. Arch Intern Med. 2002 May 27;162(10):1117-21. Open reference URL https://web.pathway.md/studies/recfKpFpUS7ACpKIW 2/2

6/29/23, 11:57 PM SYNTAX Pathway Feedback Search Clinical Topics Home Studies SYNTAX SYNTAX Disease Coronary artery disease Trial question Is PCI noninferior to CABG in patients with three-vessel or left main coronary artery disease? Study design Multi-center Open label RCT Population Characteristics of study participants 22.0% female N = 1800 78.0% male 1800 patients (402 female, 1398 male) Inclusion criteria: patients with three-vessel or left main coronary artery disease Key exclusion criteria: age < 21 years, previous PCI or CABG, pregnancy, ongoing acute MI, psychiatric illness or organic brain damage, single or 2-vessel disease without LM disease, or planned need for concomitant other cardiac surgery Interventions N=903 PCI (revascularization involving Taxus Express paclitaxel-eluting stents) N=897 CABG (standard contemporary techniques) Primary outcome Major adverse cardiac or cerebrovascular events at 12 months https://web.pathway.md/studies/recAMMmA1n2MbZ4cl 1/2 6/29/23, 11:57 PM SYNTAX Pathway 17.8 % 17.8 13.4 % 12.4 8.9 % Difference exceeding nonferiority margin 4.5 % 0.0 % Percutaneous coronary intervention Coronary artery bypass graft Difference exceeding nonferiority margin in major adverse cardiac or cerebrovascular events at 12 months (17.8% vs. 12.4%; RR 1.44, 95% CI 1.15 to 1.81) Secondary outcomes Significant increase in repeat revascularization (13.5% vs. 5.9%; RR 2.29, 95% CI 1.67 to 3.14) Significant decrease in stroke (0.6% vs. 2.2%; RR 0.25, 95% CI 0.09 to 0.67) No significant difference in death (4.4% vs. 3.5%; RR 1.24, 95% CI 0.78 to 1.98) Conclusion In patients with three-vessel or left main coronary artery disease, PCI was not noninferior to CABG with respect to major adverse cardiac or cerebrovascular events at 12 months. Reference Serruys PW, Morice MC, Kappetein AP et al. Percutaneous coronary intervention versus coronary- artery bypass grafting for severe coronary artery disease. N Engl J Med. 2009 Mar 5;360(10):961- 72. Open reference URL https://web.pathway.md/studies/recAMMmA1n2MbZ4cl 2/2

6/30/23, 2:15 AM TACKLE Pathway Feedback Search Clinical Topics Home Studies TACKLE TACKLE Disease COVID 19 infection Trial question What is the role of tixagevimab-cilgavimab in non-hospitalized adults with mild to moderate COVID- 19 infection? Study design Multi-center Double blinded RCT Population Characteristics of study participants 50.0% female N = 903 50.0% male 903 patients (455 female, 448 male) Inclusion criteria: non-hospitalized adults with mild to moderate COVID-19 who were not vaccinated Key exclusion criteria: history of hospitalization or currently hospitalized for COVID-19; a current need for hospitalization or immediate medical attention in a clinic or emergency room service Interventions N=452 tixagevimab-cilgavimab (intramuscular injection at a dose of 600 mg) N=451 placebo (intramuscular injection of 0.9% sodium chloride) Primary outcome https://web.pathway.md/studies/recdpM4rQqUeoxbCi 1/2 6/30/23, 2:15 AM TACKLE Pathway Severe COVID-19 or death 9.0 % 9 6.8 % 4.5 % 4 Significant decrease 2.3 % NNT = 20 0.0 % Tixagevimab-cilgavimab Placebo Significant decrease in severe COVID-19 or death (4% vs. 9%; ARD -4.5, 95% CI -1.1 to -8) Secondary outcomes Significant decrease in prevention of respiratory failure (1% vs. 3%; ARD -2, 95% CI -3.87 to -0.13) Safety outcomes No significant difference in adverse events. Conclusion In non-hospitalized adults with mild to moderate COVID-19 who were not vaccinated, tixagevimab- cilgavimab was superior to placebo with respect to severe COVID-19 or death. Reference Hugh Montgomery, F D Richard Hobbs, Francisco Padilla et al. Efficacy and safety of intramuscular administration of tixagevimab cilgavimab for early outpatient treatment of COVID-19 (TACKLE): a phase 3, randomised, double-blind, placebo-controlled trial. Lancet Respir Med. 2022 Oct;10(10):985-996. Open reference URL https://web.pathway.md/studies/recdpM4rQqUeoxbCi 2/2

6/30/23, 2:15 AM TACTICS-TIMI 18 Pathway Feedback Search Clinical Topics Home Studies TACTICS TIMI 18 TACTICS TIMI 18 Disease Non-ST-elevation myocardial inf Trial question Is early invasive strategy superior to conservative (selectively invasive) strategy in patients with unstable angina and myocardial infarction without ST-segment elevation who were treated with aspirin, heparin, and the glycoprotein IIb/IIIa inhibitor tirofiban? Study design Multi-center Open label RCT Population Characteristics of study participants 34.0% female N = 2220 66.0% male 2220 patients (757 female, 1463 male) Inclusion criteria: patients with unstable angina and myocardial infarction without ST-segment elevation who were treated with aspirin, heparin, and the glycoprotein IIb/IIIa inhibitor tirofiban Key exclusion criteria: persistent ST-segment elevation, secondary angina, a history of percutaneous coronary revascularization or CABG within the preceding six months, increased risk of bleeding, severe congestive HF or cardiogenic shock, or serious systemic disease Interventions N=1114 early invasive coronary artery catheterization (routine catheterization within 4 to 48 hours and revascularization as appropriate) https://web.pathway.md/studies/recUqX5D50AlMsnZn 1/2 6/30/23, 2:15 AM TACTICS-TIMI 18 Pathway N=1106 conservative coronary artery catheterization (catheterization performed only if the patient had objective evidence of recurrent ischemia or an abnormal stress test) Primary outcome Death, nonfatal MI, or rehospitalization for an acute coronary syndrome at 6 months 19.4 % 19.4 15.9 14.5 % 9.7 % Significant decrease 4.8 % NNT = 29 0.0 % Early invasive coronary artery catheterization Conservative coronary artery catheterization Significant decrease in death, nonfatal MI, or rehospitalization for an acute coronary syndrome at 6 months (15.9% vs. 19.4%; OR 0.78, 95% CI 0.62 to 0.97) Secondary outcomes Borderline significant decrease in death or nonfatal MI at 6 months (7.3% vs. 9.5%; OR 0.74, 95% CI 0.54 to 1) Conclusion In patients with unstable angina and myocardial infarction without ST-segment elevation who were treated with aspirin, heparin, and the glycoprotein IIb/IIIa inhibitor tirofiban, early invasive coronary artery catheterization was superior to conservative coronary artery catheterization with respect to death, nonfatal MI, or rehospitalization for an acute coronary syndrome at 6 months. Reference Cannon CP, Weintraub WS, Demopoulos LA et al. Comparison of early invasive and conservative strategies in patients with unstable coronary syndromes treated with the glycoprotein IIb/IIIa inhibitor tirofiban. N Engl J Med. 2001 Jun 21;344(25):1879-87. Open reference URL https://web.pathway.md/studies/recUqX5D50AlMsnZn 2/2

6/30/23, 2:15 AM TAME Pathway Feedback Search Clinical Topics Home Studies TAME TAME Disease Disease Generalized anxiety disorder Social anxiety disorder Trial question Is mindfulness-based stress reduction noninferior to escitalopram in adults with anxiety disorders? Study design Multi-center Open label RCT Population Characteristics of study participants 75.0% female N = 208 25.0% male 208 patients (156 female, 52 male) Inclusion criteria: adults with a diagnosed anxiety disorder Key exclusion criteria: comorbid psychiatric disorder other than anxiety or depression; serious medical condition that may result in surgery/hospitalization; history of head trauma causing loss of consciousness; or ongoing cognitive impairment Interventions N=136 mindfulness-based stress reduction (mindfulness meditation group class taught in person for 8 weeks) N=140 escitalopram (flexibly dosed from 10-20 mg daily PO) Primary outcome https://web.pathway.md/studies/reckX7YnHorv6BQYf 1/2 6/30/23, 2:15 AM TAME Pathway Anxiety levels reduction as assessed with clinical global impression of severity scale 1.4 1.43 1.35 1.1 0.7 Difference not exceeding nonferiority margin 0.4 0.0 Mindfulness-based stress reduction Escitalopram Difference not exceeding nonferiority margin in anxiety levels reduction as assessed with clinical global impression of severity scale (1.35 vs. 1.43; AD -0.07, 95% CI 0.23 to 0.38) Safety outcomes Significant difference in 1 study-related adverse event (15.4% vs. 78.6%). Conclusion In adults with a diagnosed anxiety disorder, mindfulness-based stress reduction was noninferior to escitalopram with respect to anxiety levels reduction as assessed with clinical global impression of severity scale. Reference Elizabeth A Hoge, Eric Bui, Mihriye Mete et al. Mindfulness-Based Stress Reduction vs Escitalopram for the Treatment of Adults With Anxiety Disorders: A Randomized Clinical Trial. JAMA Psychiatry. 2022 Nov 9;e223679. Open reference URL https://web.pathway.md/studies/reckX7YnHorv6BQYf 2/2

6/30/23, 2:15 AM TARGET (energy-dense formulation) Pathway Feedback Search Clinical Topics Home Studies TARGET (energy-dense formulation) TARGET (energy-dense formulation) Trial question What is the role of energy-dense formulation for enteral delivery of nutrition in patients undergoing mechanical ventilation? Study design Multi-center Double blinded RCT Population Characteristics of study participants 37.4% female N = 3997 62.6% male 3997 patients (1464 female, 2493 male) Inclusion criteria: adults undergoing mechanical ventilation in ICUs Key exclusion criteria: treating clinician considered the trial enteral nutrition formula or the rate of delivery to be clinically contraindicated or inevitable death Interventions N=1971 energy dense (1.5 kcal/mL enteral nutrition for up to 28 days) N=1986 routine (1.0 kcal/mL enteral nutrition for up to 28 days) Primary outcome Rate of death from all causes within 90 days 26.8 % 26.8 25.7 20.1 % 13.4 % 6.7 % No significant difference 0.0 % https://web.pathway.md/studies/rec8VfEvkScZrmb4Z 1/2 6/30/23, 2:15 AM 0.0 % TARGET (energy-dense formulation) Pathway Energy dense Routine No significant difference in the rate of death from all causes within 90 days (26.8% vs. 25.7%; RR 1.05, 95% CI 0.94 to 1.16) Secondary outcomes No significant difference in the rate of death by day 28 (22.9% vs. 23%; RR 1, 95% CI 0.89 to 1.12) No significant difference in receipt of vasopressor support (81.1% vs. 81.4%; RR 1, 95% CI 0.97 to 1.03) No significant difference in receipt of RRT (18.9% vs. 18.5%; RR 1.02, 95% CI 0.9 to 1.16) Safety outcomes No significant differences in adverse events, serious adverse events. Significant differences in regurgitation or vomiting (18.9% vs. 15.7%), largest gastric residual volume (250 ml vs. 180 ml), increased daily blood glucose levels (225.2 mg/dL vs. 212.6 mg/dL). Conclusion In adults undergoing mechanical ventilation in ICUs, energy dense was not superior to routine with respect to the rate of death from all causes within 90 days. Reference TARGET Investigators, for the ANZICS Clinical Trials Group, Marianne Chapman et al. Energy- Dense versus Routine Enteral Nutrition in the Critically Ill. N Engl J Med. 2018 Nov 8;379(19):1823- 1834. Open reference URL https://web.pathway.md/studies/rec8VfEvkScZrmb4Z 2/2

6/30/23, 2:15 AM TARGET (sepsis) Pathway Feedback Search Clinical Topics Home Studies TARGET (sepsis) TARGET (sepsis) Disease Sepsis and septic shock Trial question Is therapeutic drug monitoring superior to continuous infusion of piperacillin/tazobactam in patients with sepsis? Study design Multi-center Single blinded RCT Population Characteristics of study participants 31.0% female N = 249 69.0% male 249 patients (77 female, 172 male) Inclusion criteria: adult patients with sepsis Key exclusion criteria: contraindications to the study drug; impaired liver function; palliative care only; pregnancy; first measurement of piperacillin concentration not possible within 24 hours after randomization Interventions N=125 therapeutic drug monitoring (continuous infusion with dosing guided by daily therapeutic drug monitoring of piperacillin) N=124 fixed dose (continuous infusion with a fixed dose of 13.5 g/day) https://web.pathway.md/studies/reclPvIUAxVaOGjGL 1/2 6/30/23, 2:15 AM TARGET (sepsis) Pathway Primary outcome Mean of daily total sequential organ failure assessment score up to day 10 8.2 points 8.2 7.9 6.1 points 4.1 points 2.0 points No significant difference 0.0 points Therapeutic drug monitoring Fixed dose No significant difference in mean of daily total sequential organ failure assessment score up to day 10 (7.9 points vs. 8.2 points; AD 0.3 points, 95% CI -0.4 to 1) Secondary outcomes No significant difference in death at day 28 (21.6% vs. 25.8%; RR 0.8, 95% CI 0.5 to 1.3) No significant difference in clinical cure (35.6% vs. 17.4%; OR 1.9, 95% CI 0.5 to 6.2) No significant difference in microbiological cure (56.3% vs. 46%; OR 2.4, 95% CI 0.7 to 7.4) Safety outcomes No significant difference in adverse events. Conclusion In adult patients with sepsis, therapeutic drug monitoring was not superior to fixed dose with respect to mean of daily total sequential organ failure assessment score up to day 10. Reference Stefan Hagel, Friedhelm Bach, Thorsten Brenner et al. Effect of therapeutic drug monitoring-based dose optimization of piperacillin/tazobactam on sepsis-related organ dysfunction in patients with sepsis: a randomized controlled trial. Intensive Care Med. 2022 Mar;48(3):311-321. Open reference URL https://web.pathway.md/studies/reclPvIUAxVaOGjGL 2/2

6/30/23, 2:15 AM TAVA Pathway Feedback Search Clinical Topics Home Studies TAVA TAVA Trial question Is tranexamic acid superior to adrenaline in controlling iatrogenic bleeding during flexible bronchoscopy? Study design Single center Double blinded RCT Population Characteristics of study participants 36.0% female N = 130 64.0% male 130 patients (47 female, 83 male) Inclusion criteria: patients with bleeding during flexible bronchoscopy that was not controlled successfully after 3 applications of 5 mL of cold saline Key exclusion criteria: all relevant relative and absolute contraindications for flexible bronchoscopy and topical use of adrenaline Interventions N=65 tranexamic acid (topical instillation of 100 mg tranexamic acid per application; receipt of up to 3 applications) N=65 adrenaline (topical instillation of 0.2 mg adrenaline per application; receipt of up to 3 applications) Primary outcome Successfully controlled bleeding 83.1 % 83.1 83.1 62.3 % 41.5 % https://web.pathway.md/studies/rec7EnyGGzTlkc8PM 1/2 6/30/23, 2:15 AM TAVA Pathway 5 % 20.8 % No significant difference 0.0 % Tranexamic acid Adrenaline No significant difference in successfully controlled bleeding (83.1% vs. 83.1%; RR 1, 95% CI -76794.23 to 76796.23) Secondary outcomes No significant difference in severe bleeding episodes (18.5% vs. 7.7%; RR 2.4, 95% CI -8.89 to 13.69) No significant difference in the number of applications needed for bleeding control after crossover (2 vs. 2.2; RR 0.91, 95% CI -2.14 to 3.96) Safety outcomes No significant difference in serious adverse events. Conclusion In patients with bleeding during flexible bronchoscopy that was not controlled successfully after 3 applications of 5 mL of cold saline, tranexamic acid was not superior to adrenaline with respect to successfully controlled bleeding. Reference Sonja Badovinac, Goran Glodi , Ivan Sabol et al. Tranexamic Acid vs Adrenaline for Controlling Iatrogenic Bleeding During Flexible Bronchoscopy: A Double-Blind Randomized Controlled Trial. Chest. 2023 Apr;163(4):985-993. Open reference URL https://web.pathway.md/studies/rec7EnyGGzTlkc8PM 2/2

6/30/23, 2:16 AM TEMPO 3:4 Pathway Feedback Search Clinical Topics Home Studies TEMPO 3 4 TEMPO 3 4 Disease Autosomal dominant polycystic Trial question What is the role of tolvaptan in patients with autosomal dominant polycystic kidney disease? Study design Multi-center Double blinded RCT Population Characteristics of study participants 48.0% female N = 1445 52.0% male 1445 patients (699 female, 746 male) Inclusion criteria: patients, 18-50 years of age, who had autosomal dominant polycystic kidney disease with a total kidney volume 750 ml and an estimated CrCl 60 mL/min Key exclusion criteria: non-compliance with therapies, unawareness of thirst, severe allergic reactions to compounds with similar chemical structure as tolvaptan, contraindications to or interference with MRI assessments, concurrent conditions or taking therapies likely to confound endpoint assessments or prevent completion of the trial Interventions N=961 tolvaptan (lowest to highest tolerated levels in a split-dose regimen of 45/15 mg, 60/30 mg, and 90/30 mg BID) N=484 placebo (matching placebo BID) https://web.pathway.md/studies/recREUjefm5CbcNSy 1/2 6/30/23, 2:16 AM TEMPO 3:4 Pathway Primary outcome Incidence of change in the total kidney volume at 3 years 5.5 % / y 5.5 4.1 % / y 2.8 2.8 % / y 1.4 % / y Significant decrease 0.0 % / y Tolvaptan Placebo Significant decrease in the incidence of change in the total kidney volume at 3 years (2.8% / y vs. 5.5% / y; ARD -2.7, 95% CI -3.3 to -2.1) Secondary outcomes Significant decrease in the incidence of worsening kidney function (2 /100 py vs. 5 /100 py; HR 0.39, 95% CI 0.26 to 0.57) Significant decrease in the incidence of kidney pain (5 /100 py vs. 7 /100 py; HR 0.64, 95% CI 0.47 to 0.89) Significant increase in the incidence of decline in kidney function, as assessed by means of the reciprocal of the serum creatinine level (-2.61 mg/mL / y vs. -3.81 mg/mL / y; AD 1.2 mg/mL / y, 95% CI 0.62 to 1.78) Safety outcomes No significant difference in adverse events. Significant difference in adverse events leading to permanent discontinuation of the trial drug (23.0% vs. 13.8%). Conclusion In patients, 18-50 years of age, who had autosomal dominant polycystic kidney disease with a total kidney volume 750 ml and an estimated CrCl 60 mL/min, tolvaptan was superior to placebo with respect to the incidence of change in the total kidney volume at 3 years. Reference Torres VE, Chapman AB, Devuyst O et al. Tolvaptan in patients with autosomal dominant polycystic kidney disease. N Engl J Med. 2012 Dec 20;367(25):2407-18. Open reference URL https://web.pathway.md/studies/recREUjefm5CbcNSy 2/2

6/30/23, 2:22 AM Teriparatide for glucocorticoid-induced osteoporosis Pathway Feedback Search Clinical Topics Home Studies Teriparatide for glucocorticoid-induced osteoporosis Teriparatide for glucocorticoid-induced osteoporosis Disease Corticosteroid-induced osteopo Trial question What is the effect of teriparatide in patients with corticosteroid-induced osteoporosis? Study design Multi-center Double blinded RCT Population Characteristics of study participants 81.0% female N = 428 19.0% male 428 patients (345 female, 83 male) Inclusion criteria: women and men with osteoporosis (ages, 22 to 89 years) who had received corticosteroids for at least 3 months (prednisone equivalent, 5 mg daily) Key exclusion criteria: unresolved skeletal diseases other than corticosteroid-induced osteoporosis, an increased risk of osteosarcoma, gastrointestinal disorders that would likely reduce tolerance of oral alendronate, or substantial renal impairment Interventions N=214 teriparatide (20 g once daily) N=214 alendronate (10 mg once daily) Primary outcome https://web.pathway.md/studies/rec399HJ3PKJElJTx 1/2 6/30/23, 2:22 AM Teriparatide for glucocorticoid-induced osteoporosis Pathway Improvement of bone mineral density at lumbar spine 7.2 % 7.2 5.4 % 3.6 % 3.4 Significant increase 1.8 % NNT = 26 0.0 % Teriparatide Alendronate Significant increase in improvement of bone mineral density at the lumbar spine (7.2% vs. 3.4%; RR 2.12, 95% CI 0.86 to 3.38) Secondary outcomes Significant decrease in vertebral fractures (0.6% vs. 6.1%; RR 0.1, 95% CI 0.03 to 0.17) Significant increase in change in bone mineral density at the total hip, at 18 months (3.8% vs. 2.4%; RR 1.59, 95% CI 0.48 to 2.7) Safety outcomes No significant differences in adverse event (85.0% vs. 79.4%, p=0.11) and serious adverse event (21.0% vs. 18.2%, p=0.44). Significant differences in hypercalcemia, at least one serum calcium level > 10.5 mg/dL (18.0% vs. 5.7%, p < 0.001). Conclusion In women and men with osteoporosis (ages, 22 to 89 years) who had received corticosteroids for at least 3 months (prednisone equivalent, 5 mg daily), teriparatide was superior to alendronate with respect to improvement of bone mineral density at the lumbar spine. Reference Saag KG, Shane E, Boonen S et al. Teriparatide or alendronate in glucocorticoid-induced osteoporosis. N Engl J Med. 2007 Nov 15;357(20):2028-39. Open reference URL https://web.pathway.md/studies/rec399HJ3PKJElJTx 2/2

6/30/23, 2:16 AM TESTING 2 Pathway Feedback Search Clinical Topics Home Studies TESTING 2 TESTING 2 Disease Immunoglobulin A nephropathy Trial question What is the role of methylprednisolone in patients with IgA nephropathy? Study design Multi-center Double blinded RCT Population Characteristics of study participants 39.0% female N = 503 61.0% male 503 patients (198 female, 305 male) Inclusion criteria: patients with IgA nephropathy, proteinuria of 1 g/day and an eGFR of 20-120 mL/min/1.73 m Key exclusion criteria: strong indication or contraindication for corticosteroid therapy; active infection; systemic immunosuppressive therapy in the previous year; uncontrolled hypertension; unstable kidney function for other reasons Interventions N=257 methylprednisolone (an oral incremental course for 6-9 months followed by weaning) N=246 placebo (matching oral placebo) Primary outcome https://web.pathway.md/studies/recpGqOotx9SswVa4 1/2 6/30/23, 2:16 AM TESTING 2 Pathway Composite outcome of sustained 40% decline in estimated glomerular filtration rate, kidney failure, or death due to kidney disease 43.1 % 43.1 32.3 % 28.8 21.6 % Significant decrease 10.8 % NNT = 7 0.0 % Methylprednisolone Placebo Significant decrease in composite outcome of sustained 40% decline in eGFR, kidney failure, or death due to kidney disease (28.8% vs. 43.1%; HR 0.53, 95% CI 0.39 to 0.72) Secondary outcomes Significant decrease in kidney failure (19.5% vs. 27.2%; HR 0.59, 95% CI 0.4 to 0.87) Safety outcomes Significant difference in serious adverse events (10.9% vs. 2.8%). Conclusion In patients with IgA nephropathy, proteinuria of 1 g/day and an eGFR of 20-120 mL/min/1.73 m , methylprednisolone was superior to placebo with respect to the composite outcome of sustained 40% decline in eGFR, kidney failure, or death due to kidney disease. Reference Jicheng Lv, Muh Geot Wong, Michelle A Hladunewich et al. Effect of Oral Methylprednisolone on Decline in Kidney Function or Kidney Failure in Patients With IgA Nephropathy: The TESTING Randomized Clinical Trial. JAMA. 2022 May 17;327(19):1888-1898. Open reference URL https://web.pathway.md/studies/recpGqOotx9SswVa4 2/2

6/30/23, 2:16 AM TESTING Pathway Feedback Search Clinical Topics Home Studies TESTING TESTING Disease Immunoglobulin A nephropathy Trial question What is the effect of oral methylprednisolone in patients with IgA nephropathy and persistent proteinuria who are at risk of progression? Study design Multi-center Double blinded RCT Population Characteristics of study participants 37.0% female N = 262 63.0% male 262 patients (96 female, 166 male) Inclusion criteria: patients with IgA nephropathy and persistent proteinuria > 1 g/d and eGFR of 20-120 mL/min/1.73 m after at least 3 months of BP control and renin-angiotensin system blockade who are at risk of progression Key exclusion criteria: strong indication or contraindication for corticosteroid therapy, or the use of systemic immunosuppressive therapy in the previous year Interventions N=136 oral methylprednisolone (0.6-0.8 mg/kg/d; maximum 48 mg/d for 2 months, with subsequent weaning over 4-6 months) N=126 placebo (matching placebo for 2 months) https://web.pathway.md/studies/rec3vInWxjLkV1Aur 1/2 6/30/23, 2:16 AM TESTING Pathway Primary outcome End-stage kidney disease, death due to kidney failure, or a 40% decline in eGFR 15.9 % 15.9 11.9 % 8.0 % 5.9 Significant decrease 4.0 % NNT = 10 0.0 % Oral methylprednisolone Placebo Significant decrease in end-stage kidney disease, death due to kidney failure, or a 40% decline in eGFR (5.9% vs. 15.9%; HR 0.37, 95% CI 0.17 to 0.85) Secondary outcomes Significant increase in death, end-stage renal disease, or 40% decline in eGFR (7.4% vs. 15.9%; ARR 8.5, 95% CI 0.7 to 16.6) No significant difference in the incidence of eGFR decline (-1.79 mL/min/1.73 m /year vs. 6.95 mL/min/1.73 m /year; MD -5.15, 95% CI -9.89 to 0.42) Safety outcomes Significant differences in serious adverse events (14.7% vs. 3.2%, p = 0.001; risk difference 11.5%, 95% CI 4.8%-18.2%), mostly due to excess serious infections (8.1% vs. 0, p < 0.001; risk difference 8.1%, 95% CI 3.5%-13.9%). Conclusion In patients with IgA nephropathy and persistent proteinuria > 1 g/d and eGFR of 20-120 mL/min/1.73 m after at least 3 months of BP control and renin-angiotensin system blockade who are at risk of progression, oral methylprednisolone was superior to placebo with respect to a end- stage kidney disease, death due to kidney failure, or a 40% decline in eGFR. Reference Lv J, Zhang H, Wong MG et al. Effect of Oral Methylprednisolone on Clinical Outcomes in Patients With IgA Nephropathy: The TESTING Randomized Clinical Trial. JAMA. 2017 Aug 1;318(5):432- 442. Open reference URL https://web.pathway.md/studies/rec3vInWxjLkV1Aur 2/2

6/30/23, 2:22 AM Testosterone Trial Pathway Feedback Search Clinical Topics Home Studies Testosterone Trial Testosterone Trial Disease Disease Male hypogonadism Testosterone deficiency Trial question What is the role of testosterone treatment in older men? Study design Multi-center Double blinded RCT Population 790 male patients Inclusion criteria: men 65 years of age with serum testosterone concentration of < 275 ng/dL and symptoms suggesting hypoandrogenism Key exclusion criteria: history of prostate cancer, a risk of all prostate cancer of > 35% or of high- grade prostate cancer of > 7% as determined according to the Prostate Cancer Risk Calculator, an IPSS (IPSS; range, 0-35, with higher scores indicating more severe symptoms of benign prostatic hyperplasia) of > 19, conditions known to cause hypogonadism, receipt of medications that alter the testosterone concentration, or high cardiovascular risk Interventions N=395 testosterone gel (AndroGel 1% with an initial dose of 5 g daily) N=395 placebo (similar application and appearance to AndroGel) Primary outcome Percentage of patients achieving an improvement of at least 50 m in 6-minute walking distance 20.3 % 20.3 15.2 % 12.1 10.2 % https://web.pathway.md/studies/rechzmUYmfxEcPmhC 1/2 6/30/23, 2:22 AM Testosterone Trial Pathway 5.1 % No significant difference 0.0 % Testosterone gel Placebo No significant difference in the percentage of patients achieving an improvement of at least 50 m in 6MWD (20.3% vs. 12.1%; OR 1.42, 95% CI 0.83 to 2.45) Secondary outcomes No significant difference in the percentage of patients achieving an improvement of least 4 points on the Functional Assessment of Chronic Illness Therapy-Fatigue scale (72.4% vs. 62.8%; OR 1.23, 95% CI 0.83 to 1.84) Safety outcomes No significant difference in rates of adverse events. Conclusion In men 65 years of age with serum testosterone concentration of < 275 ng/dL and symptoms suggesting hypoandrogenism, testosterone gel was superior to placebo with respect to the percentage of patients achieving an improvement of at least 50 m in 6MWD. Reference Snyder PJ, Bhasin S, Cunningham GR et al. Effects of Testosterone Treatment in Older Men. N Engl J Med. 2016 Feb 18;374(7):611-24. Open reference URL https://web.pathway.md/studies/rechzmUYmfxEcPmhC 2/2

6/30/23, 2:23 AM Text messages for smoking cessation Pathway Feedback Search Clinical Topics Home Studies Text messages for smoking cessation Text messages for smoking cessation Disease Tobacco use Trial question What is the role of text message-based smoking cessation intervention in adult smokers? Study design Multi-center Double blinded RCT Population Characteristics of study participants 1.0% female N = 722 99.0% male 722 patients (6 female, 716 male) Inclusion criteria: daily or weekly smokers 18 years of age who owned a mobile phone and used the app Key exclusion criteria: receipt of any smoking cessation treatment within 30 days and diagnosis of any mental illness Interventions N=360 personalized text messages (personalized text messages based on the transtheoretical model and protection motivation theory) N=362 nonpersonalized text messages (smoking cessation text message intervention developed by the US National Cancer Institute) https://web.pathway.md/studies/reck3HHaVzCYSW6mO 1/2 6/30/23, 2:23 AM Text messages for smoking cessation Pathway Primary outcome Biochemically verified continuous abstinence at 6 months 6.9 % 6.9 5.2 % 3.5 % 3 Significant increase 1.7 % NNH = 26 0.0 % Personalized text messages Nonpersonalized text messages Significant increase in biochemically verified continuous abstinence at 6 months (6.9% vs. 3%; OR 2.66, 95% CI 1.21 to 5.83) Secondary outcomes Significant increase in the rate of biochemically verified continuous abstinence at 3-6 months (14.7% vs. 7.7%; OR 2.24, 95% CI 1.32 to 3.81) Significant increase in biochemically verified 24-hour point prevalence of abstinence at 1 month among smokers with low nicotine dependence (11.8% vs. 7%; OR 2.15, 95% CI 1.05 to 4.38) Significant increase in biochemically verified 24-hour point prevalence of abstinence at 6 months among smokers with moderate and high nicotine dependence (14.7% vs. 5.3%; OR 4.17, 95% CI 1.34 to 3) Conclusion In daily or weekly smokers 18 years of age who owned a mobile phone and used the app, personalized text messages were superior to nonpersonalized text messages with respect to biochemically verified continuous abstinence at 6 months. Reference Haoxiang Lin, Yihua Liu, Hao Zhang et al. Assessment of a Text Message-Based Smoking Cessation Intervention for Adult Smokers in China: A Randomized Clinical Trial. JAMA Netw Open. 2023 Mar 1;6(3):e230301. Open reference URL https://web.pathway.md/studies/reck3HHaVzCYSW6mO 2/2

6/30/23, 2:23 AM The da Vinci Trial Pathway Feedback Search Clinical Topics Home Studies The da Vinci Trial The da Vinci Trial Trial question What is the role of early prophylactic placement of vena cava filter in patients with major trauma? Study design Multi-center Open label RCT Population Characteristics of study participants 23.0% female N = 240 77.0% male 240 patients (56 female, 184 male) Inclusion criteria: severely injured patients who had a contraindication to anticoagulant agents Key exclusion criteria: imminent death, confirmed PE on admission to the trial center, systemic anticoagulant treatment before injury, pregnancy, and unavailability of an interventional radiologist to insert the filter within 72 hours after admission Interventions N=122 vena cava filter (filter placed within the first 72 hours after admission for the injury) N=118 control (no filter placement) Primary outcome Symptomatic pulmonary embolism or death from any cause at 90 days 14.4 % 14.4 13.9 10.8 % 7.2 % 3.6 % No significant difference 0.0 % https://web.pathway.md/studies/recN8ebhFqmOSZlL3 1/2 6/30/23, 2:23 AM 0 0 % The da Vinci Trial Pathway Vena cava filter Control No significant difference in symptomatic PE or death from any cause at 90 days (13.9% vs. 14.4%; HR 0.99, 99% CI 0.51 to 1.94) Secondary outcomes No significant difference in death from any cause at 90 days (13.1% vs. 9.3%; RR 1.41, 95% CI 0.69 to 2.87) No significant difference in major bleeding at 90 days (70.5% vs. 66.1%; RR 1.07, 95% CI 0.9 to 1.27) Safety outcomes No significant difference in incidence of major and nonmajor bleeding and deep vein thrombosis in a leg. Significant difference in entrapped thrombus within the filter noted at the first attempt to remove the filter (4.9% vs. n/a). Conclusion In severely injured patients who had a contraindication to anticoagulant agents, vena cava filter was not superior to control with respect to symptomatic PE or death from any cause at 90 days. Reference Kwok M Ho, Sudhakar Rao, Stephen Honeybul et al. A Multicenter Trial of Vena Cava Filters in Severely Injured Patients. N Engl J Med. 2019 Jul 25;381(4):328-337. Open reference URL https://web.pathway.md/studies/recN8ebhFqmOSZlL3 2/2

6/30/23, 2:16 AM TICH-2 (substudy) Pathway Feedback Search Clinical Topics Home Studies TICH 2 (substudy) TICH 2 (substudy) Disease Intracerebral hemorrhage Trial question What is the role of tranexamic acid on remote cerebral ischemic lesions in acute spontaneous intracerebral hemorrhage? Study design Multi-center Double blinded RCT Population Characteristics of study participants 42.0% female N = 219 58.0% male 219 patients (93 female, 126 male) Inclusion criteria: adults with acute spontaneous intracerebral hemorrhage who underwent MRI Key exclusion criteria: intracranial hemorrhage secondary to anticoagulation; thrombolysis, contraindication to study drug; trauma or a known underlying structural abnormality Interventions N=96 tranexamic acid (1 g in 100 mL intravenous bolus, followed by 1 g in 250 mL infusion within 8 hours of hemorrhage onset) N=123 placebo (0.9% saline within 8 hours of hemorrhage onset) Primary outcome https://web.pathway.md/studies/recCq37fQ22pZ5LCi 1/2 6/30/23, 2:16 AM TICH-2 (substudy) Pathway Diffusion-weighted imaging hypertense lesions 22.8 % 22.8 20.8 17.1 % 11.4 % 5.7 % No significant difference 0.0 % Tranexamic acid Placebo No significant difference in DWI hypertense lesions (20.8% vs. 22.8%; OR 0.71, 95% CI 0.33 to 1.53) Secondary outcomes No significant difference in mean number of DWI hypertense lesions (1.75 vs. 1.81; MD -0.08, 95% CI -0.36 to 0.2) Conclusion In adults with acute spontaneous intracerebral hemorrhage who underwent MRI, tranexamic acid was not superior to placebo with respect to a DWI hypertense lesions. Reference Stefan Pszczolkowski, Nikola Sprigg, Lisa J Woodhouse et al. Effect of Tranexamic Acid Administration on Remote Cerebral Ischemic Lesions in Acute Spontaneous Intracerebral Hemorrhage: A Substudy of a Randomized Clinical Trial. JAMA Neurol. 2022 May 1;79(5):468-477. Open reference URL https://web.pathway.md/studies/recCq37fQ22pZ5LCi 2/2

6/30/23, 2:16 AM TICH-2 Pathway Feedback Search Clinical Topics Home Studies TICH 2 TICH 2 Disease Intracerebral hemorrhage Trial question What is the effect of tranexamic acid in patients with stroke due to intracerebral hemorrhage? Study design Multi-center Double blinded RCT Population Characteristics of study participants 44.0% female N = 2325 56.0% male 2325 patients (1024 female, 1301 male) Inclusion criteria: adults with intracerebral hemorrhage from acute stroke Key exclusion criteria: intracerebral hemorrhage secondary to anticoagulation, thrombolysis, trauma, or a known underlying structural abnormality; contraindication to tranexamic acid; prestroke dependence; life expectancy < 3 months; and Glasgow Coma Scale score < 5 Interventions N=1161 tranexamic acid (1 g intravenous bolus followed by another 1 g infused over 8 hours, within 8 hours of symptom onset) N=1164 placebo (normal saline 0.9% administered with an identical regimen) Primary outcome https://web.pathway.md/studies/recxZPGKPAFJM2hOK 1/2 6/30/23, 2:16 AM TICH-2 Pathway Death at 90 days 22.0 % 22 21 16.5 % 11.0 % 5.5 % No significant difference 0.0 % Tranexamic acid Placebo No significant difference in death at 90 days (22% vs. 21%; aHR 0.92, 95% CI 0.77 to 1.1) Secondary outcomes Significant decrease in change in volume of hematoma from baseline to 24 hours (3.72 mL vs. 4.9 mL; AD -1.37 mL, 95% CI -2.71 to -0.04) Significant increase in length of stay in hospital (63.12 days vs. 63.73 days; AD 1.09 days, 95% CI 0.97 to 1.24) Safety outcomes No significant differences in venous thromboembolic events, arterial occlusions, seizure, nervous system disorders, infections. Significant differences in serious adverse events by day 2 (33% vs. 36%), day 7 (39% vs. 43%), 90 days (45% vs. 48%). Conclusion In adults with intracerebral hemorrhage from acute stroke, tranexamic acid was not superior to placebo with respect to death at 90 days. Reference Nikola Sprigg, Katie Flaherty, Jason P Appleton et al. Tranexamic acid for hyperacute primary IntraCerebral Haemorrhage (TICH-2): an international randomised, placebo-controlled, phase 3 superiority trial. Lancet. 2018 May 26;391(10135):2107-2115. Open reference URL https://web.pathway.md/studies/recxZPGKPAFJM2hOK 2/2

6/30/23, 2:23 AM Tick Bite Pathway Feedback Search Clinical Topics Home Studies Tick Bite Tick Bite Disease Tick bite Trial question What is the role of prophylaxis with single-dose doxycycline after an Ixodes scapularis tick bite? Study design Multi-center Double blinded RCT Population Characteristics of study participants 47.0% female N = 482 53.0% male 482 patients (225 female, 257 male) Inclusion criteria: patients who an Ixodes scapularis tick removed from their bodies within the previous 72 hours Key exclusion criteria: clinical signs of Lyme disease at the time of enrollment, receipt of antibiotics effective against Borrelia burgdorferi, vaccination against Lyme disease Interventions N=235 doxycycline (two 100 mg capsules) N=247 placebo (two identical-appearing lactose capsules) Primary outcome Development of erythema migrans at site of tick bite https://web.pathway.md/studies/recWmK4sAaJx32nao 1/2 6/30/23, 2:23 AM Tick Bite Pathway 3.2 % 3.2 2.4 % 1.6 % Significant decrease 0.8 % NNT = 36 0.4 0.0 % Doxycycline Placebo Significant decrease in development of erythema migrans at the site of tick bite (0.4% vs. 3.2%; RR 0.13, 95% CI 0.01 to 0.25) Secondary outcomes No significant difference in acute viral-like illness without erythema migrans (0.4% vs. 0.8%; ARD -0.4, 95% CI -56.9 to 56.1) No significant difference in febrile episodes (2.1% vs. 1.6%; AD 0.5%, 95% CI -2.42 to 3.42) Safety outcomes No significant differences in abdominal discomfort, diarrhea, dizziness. Significant differences in adverse events, which were more common in patients receiving doxycycline (30.1% vs. 11.1%). Conclusion In patients who an Ixodes scapularis tick removed from their bodies within the previous 72 hours, doxycycline was superior to placebo with respect to development of erythema migrans at the site of tick bite. Reference R B Nadelman, J Nowakowski, D Fish et al. Prophylaxis with single-dose doxycycline for the prevention of Lyme disease after an Ixodes scapularis tick bite. N Engl J Med. 2001 Jul 12;345(2):79-84. Open reference URL https://web.pathway.md/studies/recWmK4sAaJx32nao 2/2

6/30/23, 2:17 AM TIMACS Pathway Feedback Search Clinical Topics Home Studies TIMACS TIMACS Disease Disease Coronary artery disease Non-ST-elevation myocardial inf Trial question What is the role of early invasive intervention in patients with acute coronary syndromes? Study design Multi-center Open label RCT Population Characteristics of study participants 35.0% female N = 3031 65.0% male 3031 patients (1050 female, 1981 male) Inclusion criteria: patients with acute coronary syndromes Key exclusion criteria: not a suitable candidate for coronary revascularization, comorbidity with life expectancy < 6 months, or age < 21 years Interventions N=1593 early intervention (coronary angiography 24 hours after randomization) N=1438 delayed intervention (coronary angiography 36 hours after randomization) Primary outcome Death, myocardial infarction, or stroke at 6 months 11.3 % 11.3 https://web.pathway.md/studies/recCxNlqrEEfp7hH1 1/2 6/30/23, 2:17 AM TIMACS Pathway 3 9.6 8.5 % 5.7 % 2.8 % No significant difference 0.0 % Early intervention Delayed intervention No significant difference in death, myocardial infarction, or stroke at 6 months (9.6% vs. 11.3%; HR 0.85, 95% CI 0.68 to 1.06) Secondary outcomes Significant decrease in death, myocardial infarction, or refractory ischemia at 6 months (9.5% vs. 12.9%; HR 0.72, 95% CI 0.58 to 0.89) Significant decrease in death, myocardial infarction, or refractory ischemia at 6 months in high-risk patients (13.9% vs. 21%; HR 0.65, 95% CI 0.48 to 0.89) No significant difference in death, myocardial infarction, or refractory ischemia at 6 months in low- to-intermediate risk patients (7.6% vs. 6.7%; HR 1.12, 95% CI 0.81 to 1.56) Safety outcomes No significant differences in major bleeding, intracranial hemorrhage, need for surgical intervention to stop bleeding, or retroperitoneal hemorrhage. Conclusion In patients with acute coronary syndromes, early intervention was not superior to delayed intervention with respect to death, myocardial infarction, or stroke at 6 months. Reference Mehta SR, Granger CB, Boden WE et al. Early versus delayed invasive intervention in acute coronary syndromes. N Engl J Med. 2009 May 21;360(21):2165-75. Open reference URL https://web.pathway.md/studies/recCxNlqrEEfp7hH1 2/2

6/30/23, 2:17 AM TIME Pathway Feedback Search Clinical Topics Home Studies TIME TIME Disease Hypertension Trial question Is evening dosing of antihypertensive therapy superior to morning dosing in patients with hypertension treated with their usual antihypertensive medications? Study design Multi-center Open label RCT Population Characteristics of study participants 42.0% female N = 21104 58.0% male 21104 patients (8968 female, 12136 male) Inclusion criteria: adults with hypertension and taking 1 antihypertensive medication Key exclusion criteria: regular overnight shift work; use of antihypertensive medications at > 1 dosing time daily Interventions N=10503 evening dosing (administration of antihypertensive medications between 20:00 and 00:00) N=10601 morning dosing (administration of antihypertensive medications between 06:00 and 10:00) https://web.pathway.md/studies/recuRPIW8A3S55hte 1/2 6/30/23, 2:17 AM TIME Pathway Primary outcome Vascular death or hospitalization for nonfatal myocardial infarction or nonfatal stroke 3.7 % 3.7 3.4 2.8 % 1.9 % 0.9 % No significant difference 0.0 % Evening dosing Morning dosing No significant difference in vascular death or hospitalization for nonfatal myocardial infarction or nonfatal stroke (3.4% vs. 3.7%; HR 0.95, 95% CI 0.83 to 1.1) Secondary outcomes No significant difference in hospitalization for nonfatal myocardial infarction (1.3% vs. 1.4%; HR 0.92, 95% CI 0.73 to 1.16) No significant difference in hospitalization for nonfatal stroke (1.2% vs. 1.3%; HR 0.93, 95% CI 0.73 to 1.18) No significant difference in death from all causes (4.2% vs. 4.1%; HR 1.04, 95% CI 0.91 to 1.18) Safety outcomes No significant differences in fractures, glaucoma. Significant differences in falls (21.1% vs. 22.2%, 1 prespecified symptom adverse events (69.2% vs. 70.5%). Conclusion In adults with hypertension and taking 1 antihypertensive medication, evening dosing was not superior to morning dosing with respect to vascular death or hospitalization for nonfatal myocardial infarction or nonfatal stroke. Reference Isla S Mackenzie, Amy Rogers, Neil R Poulter et al. Cardiovascular outcomes in adults with hypertension with evening versus morning dosing of usual antihypertensives in the UK (TIME study): a prospective, randomised, open-label, blinded-endpoint clinical trial. Lancet. 2022 Oct 22;400(10361):1417-1425. Open reference URL https://web.pathway.md/studies/recuRPIW8A3S55hte 2/2

6/30/23, 2:23 AM Timing of endoscopy for AUGB Pathway Feedback Search Clinical Topics Home Studies Timing of endoscopy for AUGB Timing of endoscopy for AUGB Disease Disease Non-variceal upper gastrointesti Variceal hemorrhage Trial question What is the role of urgent endoscopy in patients with acute upper gastrointestinal bleeding who are at high risk for further bleeding or death? Study design Single center Open label RCT Population Characteristics of study participants 37.0% female N = 516 63.0% male 516 patients (191 female, 325 male) Inclusion criteria: patients with overt signs of acute upper gastrointestinal bleeding and a Glasgow-Blatchford score 12 Key exclusion criteria: continued shock despite initial volume resuscitation, age < 18 years, unable to provide written informed consent, pregnant or lactating women, moribund from terminal illnesses Interventions N=258 urgent-endoscopy (endoscopy within 6 hours of gastroenterology consultation) N=258 early-endoscopy (endoscopy between 6 and 24 hours after gastroenterology consultation) https://web.pathway.md/studies/recySAXe7DUlbYPzI 1/2 6/30/23, 2:23 AM Timing of endoscopy for AUGB Pathway Primary outcome Death from any cause at 30 days 8.9 % 8.9 6.7 % 6.6 4.5 % 2.2 % No significant difference 0.0 % Urgent-endoscopy Early-endoscopy No significant difference in death from any cause at 30 days (8.9% vs. 6.6%; HR 1.35, 95% CI 0.72 to 2.54) Secondary outcomes No significant difference in the rate of further bleeding within 30 days (10.9% vs. 7.8%; HR 1.46, 95% CI 0.83 to 2.58) No significant difference in ICU admission (1.6% vs. 1.2%; HR 1.33, 95% CI 0.3 to 5.9) Borderline significant increase in endoscopic hemostatic treatment during initial endoscopy (60.1% vs. 48.4%; HR 1.24, 95% CI 1.06 to 1.46) Safety outcomes No significant differences in persistent bleeding, recurrent bleeding, fatal and nonfatal adverse events. Significant difference in ulcers with active bleeding or visible vessels (66.4% vs. 47.8%). Conclusion In patients with overt signs of acute upper gastrointestinal bleeding and a Glasgow-Blatchford score 12, urgent-endoscopy was not superior to early-endoscopy with respect to death from any cause at 30 days. Reference James Y W Lau, Yuanyuan Yu, Raymond S Y Tang et al. Timing of Endoscopy for Acute Upper Gastrointestinal Bleeding. Reply. N Engl J Med. 2020 Apr 2;382(14):1299-1308. Open reference URL https://web.pathway.md/studies/recySAXe7DUlbYPzI 2/2

6/30/23, 2:17 AM TITAN Pathway Feedback Search Clinical Topics Home Studies TITAN TITAN Disease Thrombotic thrombocytopenic p Trial question What is the effect of caplacizumab in patients with acquired TTP? Study design Multi-center Single blinded RCT Population Characteristics of study participants 59.0% female N = 75 41.0% male 75 patients (44 female, 31 male) Inclusion criteria: patients with an acute episode of acquired TTP with a platelet count of < 100,000/ L, without active bleeding, and who required plasma exchange Key exclusion criteria: platelet count 100,000/ L, severe active infection, antiphospholipid syndrome, DIC, pregnant or breastfeeding, hematopoietic stem cell or BMT-associated thrombotic microangiopathy, known congenital TTP, active bleeding or high risk of bleeding, uncontrolled arterial hypertension. Interventions N=36 caplacizumab (10 mg SC once daily during plasma exchange and for 30 days afterward) N=39 placebo (SC daily during plasma exchange daily and for 30 days afterward) https://web.pathway.md/studies/rec8rjup5T3QnSLAz 1/2 6/30/23, 2:17 AM TITAN Pathway Primary outcome Median time to response 4.9 days 4.9 3.7 days 3 2.5 days 1.2 days Significant decrease 0.0 days Caplacizumab Placebo Significant decrease in median time to response (3 days vs. 4.9 days; RR 0.61, 95% CI 0.18 to 1.04) Safety outcomes No significant difference in total adverse events. Significant difference in mild-to-moderate bleeding-related adverse events (54% vs. 38%). Conclusion In patients with an acute episode of acquired TTP with a platelet count of < 100,000/ L, without active bleeding, and who required plasma exchange, caplacizumab was superior to placebo with respect to median time to response. Reference Peyvandi F, Scully M, Kremer Hovinga JA et al. Caplacizumab for Acquired Thrombotic Thrombocytopenic Purpura. N Engl J Med. 2016 Feb 11;374(6):511-22. Open reference URL https://web.pathway.md/studies/rec8rjup5T3QnSLAz 2/2

6/30/23, 2:17 AM TNT Pathway Feedback Search Clinical Topics Home Studies TNT TNT Disease Disease Coronary artery disease Dyslipidemia Trial question Is 80 mg atorvastatin superior to 10 mg atorvastatin in patients with stable coronary disease and LDL cholesterol levels of < 130 mg/dL? Study design Multi-center Double blinded RCT Population Characteristics of study participants 19.0% female N = 10001 81.0% male 10001 patients (1902 female, 8099 male) Inclusion criteria: patients with stable coronary disease and LDL cholesterol levels of < 130 mg/dL Key exclusion criteria: hypersensitivity to statins; active liver disease or hepatic dysfunction; pregnant or breastfeeding women; nephrotic syndrome; uncontrolled diabetes mellitus; uncontrolled hypothyroidism; or uncontrolled hypertension Interventions N=4995 high-dose atorvastatin (80 mg of atorvastatin) N=5006 low-dose atorvastatin (10 mg of atorvastatin) Primary outcome https://web.pathway.md/studies/recw13EEFzbOERu7Z 1/2 6/30/23, 2:17 AM TNT Pathway Major cardiovascular events 10.9 % 10.9 8.7 8.2 % 5.5 % Significant decrease 2.7 % NNT = 45 0.0 % High-dose atorvastatin Low-dose atorvastatin Significant decrease in major cardiovascular events (8.7% vs. 10.9%; HR 0.78, 95% CI 0.69 to 0.89) Secondary outcomes Significant decrease in major coronary events (6.7% vs. 8.3%; HR 0.8, 95% CI 0.69 to 0.92) No significant difference in death from any cause (5.7% vs. 5.6%; HR 1.01, 95% CI 0.85 to 1.19) Significant decrease in cerebrovascular event (3.9% vs. 5%; HR 0.77, 95% CI 0.64 to 0.93) Safety outcomes Significant differences in adverse events (8.1% vs. 5.8%, p < 0.001), including persistent elevations in liver aminotransferase levels (1.2% vs. 0.2%, p < 0.001). Conclusion In patients with stable coronary disease and LDL cholesterol levels of < 130 mg/dL, high-dose atorvastatin was superior to low-dose atorvastatin with respect to major cardiovascular events. Reference LaRosa JC, Grundy SM, Waters DD et al. Intensive lipid lowering with atorvastatin in patients with stable coronary disease. N Engl J Med. 2005 Apr 7;352(14):1425-35. Open reference URL https://web.pathway.md/studies/recw13EEFzbOERu7Z 2/2

6/30/23, 2:17 AM TOBOGM Pathway Feedback Search Clinical Topics Home Studies TOBOGM TOBOGM Disease Diabetes during pregnancy Trial question What is the role of immediate treatment of gestational diabetes before 20 weeks gestation? Study design Multi-center Open label RCT Population 802 female patients Inclusion criteria: women between 4 weeks and 19 weeks 6 days gestation who had a risk factor for hyperglycemia and a diagnosis of gestational diabetes Key exclusion criteria: pre-existing diabetes; fasting glucose level 110 mg/dL; or a 2-hour glucose level 200 mg/dL Interventions N=406 immediate treatment (education, dietary advice and instructions on how to monitor capillary blood glucose levels) N=396 no treatment (no treatment or deferred treatment) Primary outcome Adverse neonatal outcome 30.5 % 30.5 24.9 22.9 % 15.3 % Significant decrease 7.6 % NNT = 18 0 0 % https://web.pathway.md/studies/reciu1rTeQnpQ2Zhk 1/2 6/30/23, 2:17 AM 0.0 % TOBOGM Pathway Immediate treatment No treatment Significant decrease in adverse neonatal outcome (24.9% vs. 30.5%; RR 0.82, 95% CI 0.68 to 0.98) Secondary outcomes No significant difference in pregnancy-related hypertension (10.6% vs. 9.9%; RR 1.08, 95% CI 0.85 to 1.38) No significant difference in mean neonatal lean body mass (2.86 kg vs. 2.91 kg; AD -0.04 kg, 95% CI -0.09 to 0.02) Borderline significant decrease in perineal injury (0.8% vs. 3.6%; RR 0.23, 95% CI 0.1 to 0.51) Safety outcomes No significant difference in serious adverse events. Conclusion In women between 4 weeks and 19 weeks 6 days gestation who had a risk factor for hyperglycemia and a diagnosis of gestational diabetes, immediate treatment was superior to no treatment with respect to adverse neonatal outcome. Reference David Simmons, Jincy Immanuel, William M Hague et al. Treatment of Gestational Diabetes Mellitus Diagnosed Early in Pregnancy. N Engl J Med. 2023 Jun 8;388(23):2132-2144. Open reference URL https://web.pathway.md/studies/reciu1rTeQnpQ2Zhk 2/2

6/30/23, 2:17 AM TOCIBRAS Pathway Feedback Search Clinical Topics Home Studies TOCIBRAS TOCIBRAS Disease COVID 19 infection Trial question What is the role of tocilizumab in patients with severe or critical COVID-19 infection? Study design Multi-center Open label RCT Population Characteristics of study participants 32.0% female N = 129 68.0% male 129 patients (41 female, 88 male) Inclusion criteria: adult patients with COVID-19 infection who were receiving supplemental oxygen or mechanical ventilation and had abnormal levels of at least two serum biomarkers (CRP, D- dimer, LDH, or ferritin) Key exclusion criteria: hypersensitivity to tocilizumab, active uncontrolled infections, low neutrophils count, low platelets count, liver disease, cirrhosis or elevated AST or ALT above 5 times the upper limit, renal disease with estimate glomerular filtration below 30 mL/min/1.72 m , active diverticulitis Interventions N=65 tocilizumab (single intravenous infusion of 8 mg/kg plus standard care) N=64 standard of care (standard care alone) https://web.pathway.md/studies/recjZNcO4EdpvPfbp 1/2 6/30/23, 2:17 AM TOCIBRAS Pathway Primary outcome Death or mechanical ventilation at 15 days 28.0 % 28 21.0 % 20 14.0 % 7.0 % No significant difference 0.0 % Tocilizumab Standard of care No significant difference in death or mechanical ventilation at 15 days (28% vs. 20%; OR 1.54, 95% CI 0.66 to 3.66) Secondary outcomes No significant difference in death at 28 days (21% vs. 9%; OR 2.7, 95% CI 0.97 to 8.35) Significant increase in death in the hospital (21% vs. 9%; OR 2.7, 95% CI 0.97 to 8.35) Safety outcomes No significant difference in adverse events (43% vs. 34%) and serious adverse events (16% vs. 11%). Conclusion In adult patients with COVID-19 infection who were receiving supplemental oxygen or mechanical ventilation and had abnormal levels of at least two serum biomarkers (CRP, D-dimer, LDH, or ferritin), tocilizumab was not superior to standard of care with respect to death or mechanical ventilation at 15 days. Reference Viviane C Veiga, Jo o A G G Prats, Danielle L C Farias et al. Effect of tocilizumab on clinical outcomes at 15 days in patients with severe or critical coronavirus disease 2019: randomised controlled trial. BMJ. 2021 Jan 20;372:n84. Open reference URL https://web.pathway.md/studies/recjZNcO4EdpvPfbp 2/2

6/30/23, 2:17 AM TOGETHER (fluvoxamine plus inhaled budesonide) Pathway Feedback Search Clinical Topics Home Studies TOGETHER (fluvoxamine plus inhaled budesonide) TOGETHER (fluvoxamine plus inhaled budesonide) Disease COVID 19 infection Trial question What is the role of oral fluvoxamine plus inhaled budesonide in high-risk outpatients with early COVID-19? Study design Multi-center Double blinded RCT Population Characteristics of study participants 61.0% female N = 1476 39.0% male 1476 patients (898 female, 578 male) Inclusion criteria: symptomatic adults with COVID-19 and a known risk factor for progression to severe disease Key exclusion criteria: acute respiratory symptoms due to other causes; diagnostic test for negative COVID-19 associated with acute flu symptoms; dyspnea secondary to other acute and chronic respiratory causes or infections Interventions N=738 fluvoxamine-budesonide (an oral dose of fluvoxamine 100 mg BID plus inhaled budesonide 800 g BID for 10 days) N=738 placebo (matching placebos) https://web.pathway.md/studies/recfxKUeN0lTfxDLA 1/2 6/30/23, 2:17 AM TOGETHER (fluvoxamine plus inhaled budesonide) Pathway Primary outcome Emergency setting for COVID-19 for > 6 hours or hospitalization due to COVID-19 3.7 % 3.7 2.8 % 1.9 % 1.8 0.9 % Borderline significant decrease 0.0 % Fluvoxamine-budesonide Placebo Borderline significant decrease in emergency setting for COVID-19 for > 6 hours or hospitalization due to COVID-19 (1.8% vs. 3.7%; RR 0.5, 95% CI 0.25 to 0.92) Secondary outcomes No significant difference in health care attendance (2.6% vs. 4.1%; RR 0.64, 95% CI 0.36 to 1.11) No significant difference in any emergency setting visit (12.2% vs. 13%; RR 0.94, 95% CI 0.72 to 1.22) No significant difference in death due to COVID-19 (RR 2.44, 95% CI 0.18 to 76.66) Safety outcomes No significant difference in treatment-emergent adverse event. Conclusion In symptomatic adults with COVID-19 and a known risk factor for progression to severe disease, fluvoxamine-budesonide was superior to placebo with respect to emergency setting for COVID-19 for > 6 hours or hospitalization due to COVID-19. Reference Gilmar Reis, Eduardo Augusto Dos Santos Moreira Silva, Daniela Carla Medeiros Silva et al. Oral Fluvoxamine With Inhaled Budesonide for Treatment of Early-Onset COVID-19 : A Randomized Platform Trial. Ann Intern Med. 2023 May;176(5):667-675. Open reference URL https://web.pathway.md/studies/recfxKUeN0lTfxDLA 2/2

6/30/23, 2:17 AM TOGETHER (ivermectin) Pathway Feedback Search Clinical Topics Home Studies TOGETHER (ivermectin) TOGETHER (ivermectin) Disease COVID 19 infection Trial question What is the role of early treatment with ivermectin in patients with COVID-19? Study design Multi-center Double blinded RCT Population Characteristics of study participants 58.0% female N = 1358 42.0% male 1358 patients (791 female, 567 male) Inclusion criteria: adult patients who had symptoms of COVID-19 for up to 7 days with one risk factor for disease progression Key exclusion criteria: diagnostic test for negative COVID-19 associated with acute flu symptoms; requirement of hospitalization due to COVID-19; acute respiratory symptoms due to other causes; dyspnea secondary to other acute and chronic respiratory causes or infections Interventions N=679 ivermectin (400 g/kg of body weight once daily for 3 days) N=679 placebo (matching placebo for 3 days) Primary outcome https://web.pathway.md/studies/rec9O1z2zpUFslj6a 1/2 6/30/23, 2:17 AM TOGETHER (ivermectin) Pathway Hospitalization due to COVID-19 or emergency department visits due to clinical worsening of COVID-19 at 28 days 16.3 % 16.3 14.7 12.2 % 8.2 % 4.1 % No significant difference 0.0 % Ivermectin Placebo No significant difference in hospitalization due to COVID-19 or emergency department visits due to clinical worsening of COVID-19 at 28 days (14.7% vs. 16.3%; RR 0.9, 95% CI 0.7 to 1.16) Secondary outcomes No significant difference in viral clearance at day 7 (25.4% vs. 25.5%; RR 1, 95% CI 0.68 to 1.46) No significant difference in hospitalization for any cause (11.6% vs. 14%; RR 0.83, 95% CI 0.63 to 1.1) No significant difference in death (3.1% vs. 3.5%; RR 0.88, 95% CI 0.49 to 1.55) Safety outcomes No significant difference in adverse events. Conclusion In adult patients who had symptoms of COVID-19 for up to 7 days with one risk factor for disease progression, ivermectin was not superior to placebo with respect to hospitalization due to COVID-19 or emergency department visits due to clinical worsening of COVID-19 at 28 days. Reference Gilmar Reis, Eduardo A S M Silva, Daniela C M Silva et al. Effect of Early Treatment with Ivermectin among Patients with Covid-19. N Engl J Med. 2022 May 5;386(18):1721-1731. Open reference URL https://web.pathway.md/studies/rec9O1z2zpUFslj6a 2/2